Emulsion formulations of multikinase inhibitors

ABSTRACT

Compositions comprising a therapeutically effective amount of a multikinase inhibitor, such as nintedanib or axitinib or pazopanib, are provided, wherein the composition is an emulsion, such as a nanoemulsion, with lipophilic carrier (e.g., castor oil), a polyoxyl oil (e.g., polyolyl-35 castor oil), optionally with a surfactant (e.g., polysorbate 80), optionally with a cyclic oligosaccharide, such as a cyclodextrin (e.g., 2-hydroxypropyl-beta-cyclodextrin), as a solubilizer. Methods for treating ocular conditions with the compositions are also provided.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. application Ser.No. 17/509,774, filed on Oct. 25, 2021, which is a continuationapplication of U.S. application Ser. No. 17/272,105, filed on Feb. 26,2021, which is a National Stage Application under 35 U.S.C. § 371 andclaims the benefit of International Application No. PCT/US2019/048635,filed Aug. 28, 2019, which claims the benefit of U.S. ProvisionalApplication Ser. No. 62/723,998, filed Aug. 28, 2018, the content ofwhich are incorporated herein by reference in their entireties.

TECHNICAL FIELD

Provided herein are formulations for delivery of multikinase inhibitors.

BACKGROUND

Multikinase inhibitors are inhibitors that target more than one proteinkinases. Protein kinases are enzymes that add a phosphate group to aprotein, and can modulate its function. Phosphorylation regulates manybiological processes, and multikinase inhibitors can be used to treatvarious diseases or to modulate cellular functions. The therapeuticpotential of such compounds depends, at least in part, on the extent towhich the compounds can be formulated and delivered in a way that issuitable for particular treatments.

SUMMARY

Provided herein are compositions for the delivery of multikinaseinhibitors. In some embodiments, compositions and methods for treatingone or more ocular conditions are provided.

The disclosure provides compositions for treating ocular conditions,including diseases affecting the anterior segment of the eye diseases.The composition can comprise a therapeutically effective amount of amultikinase inhibitor, such as nintedanib or axitinib or pazopanib,wherein the composition is an emulsion, such as a nanoemulsion (e.g.,comprising castor oil, polyoxyl-35 castor oil, and optionallypolysorbate 80), with a cyclic oligosaccharide, such as a cyclodextrin(e.g., 2-hydroxypropyl-beta-cyclodextrin), as a solubilizer, and issuitable for topical administration to an eye. The disclosure furtherprovides methods for treating ocular conditions with the disclosedcompositions.

In some embodiments, a composition suitable for topical administrationto an eye is provided comprising a therapeutically effective amount of amultikinase inhibitor, such as nintedanib or axitinib or pazopanib,wherein said composition comprises an emulsion, such as a nanoemulsion,with cyclodextrin, such as 2-hydroxypropyl-beta-cyclodextrin, as asolubilizer. In some embodiments, methods are provided for treating anocular condition associated with angiogenesis, such as hyperemia,neovascularization, pterygium, pinguecula, glaucoma filtration surgeryand minimally invasive glaucoma surgery (MIGS), cornea transplantsurgery with graft rejection, graft versus host disease, dry eyedisease, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell'ssyndrome, Steven Johnson syndrome, viral infection (e.g. HSV-1),bacterial infection, fungal infection, parasitic infection, contact lensinduced neovascularization, ulceration, alkali burns, and stem celldeficiency.

In one aspect, an emulsion is provided, including a therapeuticallyeffective amount of a multikinase inhibitor; a solubilizer; a lipophiliccarrier; and one or more surfactants. In one aspect, an emulsion isprovided, including a therapeutically effective amount of a multikinaseinhibitor; polyoxyl oil; a solubilizer; a lipophilic carrier; and one ormore surfactants.

This and other embodiments can optionally further include one or more ofthe following features. In some embodiments, the emulsion can be ananoemulsion. In some embodiments, the multikinase inhibitor can beselected from afatinib, amuvatinib, axitinib, cabozantinib, canertinib,cediranib, ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib,dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib,icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib,nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib,regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib,tivozanib, trametinib, vandetanib, vatalanib, vemurafenib, orcombinations thereof.

In some embodiments, the solubilizer can be a cyclic polysaccharide. Insome embodiments, the cyclic polysaccharide can be selected fromcyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin,2-hydroxypropyl-alpha-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin,2-hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrinand combinations thereof.

In some embodiments, the lipophilic carrier can be selected from castoroil, squalane, diethylene glycol monoethyl ether, propylene glycol,isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethylether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil,caprylic/capric triglycerides, medium chain triglycerides andcombinations thereof. In some embodiments, the surfactant can beselected from polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 80, polyoxyl-40-stearate, polyoxyl-35 castor oil,polyoxyl-40 castor oil, tocopherol and other polymeric emulsifiers andcombinations thereof.

In some embodiments, the multikinase inhibitor is nintedanib, thesolubilizer is 2-hydroxypropyl-beta-cyclodextrin, the lipophilic carrieris castor oil, and the surfactant is polysorbate 80, polyoxyl-35 castoroil, or a combination thereof.

In some embodiments, the multikinase inhibitor can be present in anamount of from about 0.001% w/w to about 10.0% w/w. In some embodiments,the multikinase inhibitor is nintedanib and the nintedanib can bepresent in an amount from about 0.01% w/w to about 10.0% w/w. In someembodiments, the multikinase inhibitor is axitinib, and the axitinib canbe present in the emulsion in an amount from about 0.001% w/w to about1.0% w/w. In some embodiments, the multikinase inhibitor is axitinib,and the axitinib can be present in the emulsion in an amount from about0.001% w/w to about 10.0% w/w. In some embodiments, the multikinaseinhibitor is pazopanib, and the pazopanib can be present in an amountfrom about 0.01% w/w to about 10.0% w/w. In some embodiments, thelipophilic carrier can be present in an amount from about 0.01% w/w toabout 5.0% w/w.

In some embodiments, the surfactant can be present in an amount fromabout 0.01% w/w to about 10% w/w. In some embodiments, the solubilizercan be present in the emulsion in an amount from about 1% w/w to about20% w/w.

In some embodiments, the emulsion can further comprise an additionalconstituent selected from the group consisting of a thickener, abuffering agent, a tonicity agent, an antioxidant, a preservative, andcombinations thereof. In some embodiments, the thickener can be selectedfrom the group consisting of carbomer, sodium carboxymethyl cellulose,methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol,xanthan gum, and combinations thereof. In some embodiments, thethickener can be hydroxypropyl methylcellulose or sodiumcarboxymethylcellulose, and the thickener is present in an amount fromabout 0.01% w/w to about 1.0% w/w. In some embodiments, the bufferingagent can be selected from the group consisting of phosphates, citrates,acetates, borates, and combinations thereof. In some embodiments, thebuffering agent can be selected from the group consisting of sodiumphosphate monobasic monohydrate, monosodium phosphate monohydrate,sodium phosphate dibasic heptahydrate, and boric acid, and the bufferingagent is present in the emulsion in an amount sufficient to maintain thepH in the range of 4.0 to 8.0. In some embodiments, the antioxidant canbe selected from the group consisting of edetate disodium,dibutylhydroxytoluene, citric acid, sodium metabisulfite, tocopherolacetate, and combinations thereof. In some embodiments, the antioxidantcan be edetate disodium, and the antioxidant is present in an amountfrom about 0.01% w/w to about 1.0% w/w. In some embodiments, thetonicity agent can be selected from the group consisting of sodiumchloride, glycerin, mannitol, potassium chloride, erythritol, andcombinations thereof. In some embodiments, the tonicity agent can beglycerin, and the tonicity agent is present in an amount from about 0.1%w/w to about 10% w/w. In some embodiments, the tonicity agent can bepresent in an amount sufficient to maintain the osmolarity in the rangeof 250 to 400 mOsm/kg.

In some embodiments, the emulsion can be free of preservatives. In someembodiments, the emulsion can further comprise a preservative selectedfrom the group consisting of BAK, PHMB, Purite®, sorbic acid, andcombinations thereof.

In some embodiments, the emulsion can have an average droplet size offrom about 10 nm to 100,000 nm. In some embodiments, the emulsion canhave an average droplet size of 200 nm or less. In some embodiments, theemulsion can have an average droplet size of about 100 nm or less. Insome embodiments, the emulsion can have an average droplet size of about75 nm or less. In some embodiments, the emulsion can have an averagedroplet size of about 25 to about 200 nm (e.g., about 25 to about 150nm, about 25 to about 100 nm, about 25 to about 75 nm, about 50 to about200 nm, about 50 to about 150 nm, or about 50 to about 100 nm). Withoutbeing bound by any particular theory, it is believed that, at least forsome emulsions (e.g., those described herein), a smaller droplet sizecan lead to a longer time to phase separation of an emulsion and/or alonger stability time of the emulsion. Similarly, without being bound byany particular theory, it is believed that, at least for some emulsions(e.g., those described herein), a smaller droplet size can increase thetransparency of the emulsion, for example, an emulsion having a smalldroplet size (e.g., about 50 nm) can be almost clear, while a largerdroplet size, or an emulsion that has separated, can be milky inappearance.

In some embodiments, the emulsion can remain stable for at least 6months at 25° C. In some embodiments, the emulsion can remain stable forat least 12 months at 25° C. In some embodiments, the emulsion canremain stable for at least 24 months at 25° C. In some embodiments, theemulsion can remain stable for at least 1 month at 40° C. In someembodiments, the emulsion can remain stable for at least 2 months at 40°C.

In some embodiments, the emulsion can be formulated as an eyedrop, acream, a gel, and ointment, a film, or a sustained release implant. Inanother aspect, a method is provided for prolonging the residence timeof a multikinase inhibitor in the ocular surface comprisingadministering the any one or more of the emulsions described herein toan eye of a subject. In some embodiments, the administering can compriseapplying the emulsion to the eye at least once per day. In someembodiments, the administering can comprise applying the emulsion to theeye at least twice per day. In some embodiments, the administering cancomprise applying the emulsion to the eye at least three times per day.

In another aspect, a method is provided for treating an ocularcondition, comprising administering any one or more of the emulsionsdescribed herein to an eye of a subject. In some embodiments, the ocularcondition can be associated with angiogenesis. In some embodiments, theocular condition can be selected from hyperemia, neovascularization,pterygium, pinguecula, glaucoma filtration surgery and minimallyinvasive glaucoma surgery (MIGS), cornea transplant surgery with graftrejection, graft versus host disease, dry eye disease, atopicconjunctivitis, rosacea, ocular pemphigoid, Lyell's syndrome, StevenJohnson syndrome, viral infection (e.g. HSV-1), bacterial infection,fungal infection, parasitic infection, contact lens inducedneovascularization, ulceration, alkali burns, and stem cell deficiency.

In another aspect, provided herein is an emulsion comprising atherapeutically effective amount of a multikinase inhibitor, a polyoxyloil, a lipophilic carrier, and water.

Implementations can include one or more of the following features. Theemulsion can be a nanoemulsion. The multikinase inhibitor can beselected from afatinib, amuvatinib, axitinib, cabozantinib, canertinib,cediranib, ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib,dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib,icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib,nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib,regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib,tivozanib, trametinib, vandetanib, vatalanib, vemurafenib, orcombinations thereof. The multikinase inhibitor can be selected fromaxitinib, nintedanib, and pazopanib. The multikinase inhibitor can beaxitinib. The multikinase inhibitor can be nintedanib. The multikinaseinhibitor can be pazopanib. The emulsion can further include asolubilizer. The solubilizer can be a cyclic polysaccharide. The cyclicpolysaccharide can be selected from the group consisting ofcyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin,2-hydroxypropyl-alpha-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin,2-hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrinand combinations thereof. The polyoxyl oil can be a polyoxyl castor oil.The polyoxyl castor oil can be polyoxyl-40 castor oil, polyoxyl-35castor oil, or a combination thereof. The lipophilic carrier can beselected from the group consisting of castor oil, squalane, diethyleneglycol monoethyl ether, propylene glycol, isostearyl isostearate,isopropyl myristate, dipropylene glycol dimethyl ether, diethyleneglycol, dipropylene glycol, mineral oil, silicone oil, caprylic/caprictriglycerides, medium chain triglycerides and combinations thereof. Theemulsion can further include a surfactant selected from the groupconsisting of polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 80, polyoxyl-40-stearate, tocopherol, and combinationsthereof. The multikinase inhibitor can be nintedanib, the solubilizercan be 2-hydroxypropyl-beta-cyclodextrin, the lipophilic carrier can becastor oil, and the polyoxyl oil can be polyoxyl-35 castor oil, or acombination thereof. The multikinase inhibitor can be present in anamount from about 0.001% w/w to about 10.0% w/w. The multikinaseinhibitor can be present in an amount of about 0.01% to about 1% w/w.The multikinase inhibitor can be present in an amount of about 0.1% toabout 0.5% w/w. The multikinase inhibitor can be nintedanib and thenintedanib can be present in an amount from about 0.01% w/w to about10.0% w/w. The nintedanib can be present in an amount from about 0.01%to about 1% w/w. The nintedanib can be present in an amount from about0.1% to about 0.5% w/w. The multikinase inhibitor can be axitinib, andthe axitinib can be present in the emulsion in an amount from about0.001% w/w to about 10.0% w/w. The axitinib can be present in an amountfrom about 0.01% to about 1% w/w. The axitinib can be present in anamount from about 0.1% to about 0.5% w/w. The axitinib can be present inan amount from about 0.05% to about 0.5% w/w. The multikinase inhibitorcan be pazopanib, and the pazopanib can be present in an amount fromabout 0.01% w/w to about 10.0% w/w. The pazopanib can be present in anamount from about 0.01% to about 1% w/w. The pazopanib can be present inan amount from about 0.1% to about 0.5% w/w. The lipophilic carrier canbe present in an amount from about 0.01% w/w to about 5.0% w/w. Thelipophilic carrier can be present in an amount from about 0.05% to about1% w/w. The lipophilic carrier can be present in an amount from about0.1% to about 0.5% w/w. The polyoxyl oil can be present in an amountfrom about 0.01% w/w to about 10% w/w. The polyoxyl oil can be presentin an amount from about 0.05% to about 1% w/w. The polyoxyl oil can bepresent in an amount from about 0.1% to about 0.5% w/w. The emulsion canfurther include a solubilizer, wherein the solubilizer can be present inthe emulsion in an amount from about 1% w/w to about 20% w/w. Thesolubilizer can be present in an amount from about 5% to about 15% w/w.The solubilizer can be present in an amount from about 8% to about 12%w/w. The emulsion can further include an additional constituent selectedfrom the group consisting of a thickener, a buffering agent, a tonicityagent, an antioxidant, and combinations thereof. The thickener can beselected from the group consisting of carbomer, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinylalcohol, xanthan gum, and combinations thereof. The thickener can behydroxypropyl methylcellulose, sodium carboxymethylcellulose, or acombination thereof. The thickener can be present in an amount fromabout 0.01% w/w to about 1.0% w/w. The thickener can be present in anamount from about 0.05% w/w to about 0.5% w/w. The buffering agent canbe selected from the group consisting of phosphates, citrates, acetates,borates, and combinations thereof. The buffering agent can be selectedfrom the group consisting of sodium citrate dihydrate, sodium citrate,sodium phosphate monobasic monohydrate, monosodium phosphatemonohydrate, sodium phosphate dibasic heptahydrate, boric acid, andcombinations thereof. The buffering agent can be selected from the groupconsisting of sodium citrate dihyrdrate, sodium citrate, or acombination thereof. The buffering agent can be present in the emulsionin an amount sufficient to maintain the pH in the range of 4.0 to 8.0.The buffering agent can be present in the emulsion in an amountsufficient to maintain the pH in the range of about 5.5 to about 6.5.The buffering agent can be present in an amount of about 0.01% w/w toabout 1.0% w/w. The buffering agent can be present in an amount of about0.03% w/w to about 0.06% w/w. The antioxidant can be selected from thegroup consisting of edetate disodium, dibutylhydroxytoluene, citricacid, sodium metabisulfite, tocopherol acetate, and combinationsthereof. The antioxidant can be selected from the group consisting ofedetate disodium, citric acid, and combinations thereof. The antioxidantcan be present in an amount from about 0.01% to about 1.0% w/w. Theantioxidant can be present in an amount from about 0.05% to about 0.5%w/w. The antioxidant can include edetate disodium, and the edetatedisodium can be present in an amount from about 0.01% % w/w to about1.0% w/w. The antioxidant can include edetate disodium, and the edetatedisodium can be present in an amount from about 0.05 w/w to about 0.5w/w. The antioxidant can include citric acid, and the citric acid can bepresent in an amount from about 0.001% to about 0.1% w/w. Theantioxidant can include citric acid, and the citric acid can be presentin an amount from about 0.005% to about 0.05% w/w. The tonicity agentcan be selected from the group consisting of sodium chloride, glycerin,mannitol, potassium chloride, erythritol, and combinations thereof. Thetonicity agent can be glycerin. The tonicity agent can be present in anamount from about 0.1% w/w to about 10% w/w. The tonicity agent can bepresent in an amount from about 0.01% w/w to about 1% w/w. The tonicityagent can be present in an amount from about 0.05% w/w to about 0.5%w/w. The tonicity agent can be present in an amount sufficient tomaintain the osmolarity in the range of 250 to 400 mOsm/kg. The emulsioncan further include a preservative. The preservative can be selectedfrom the group consisting of benzalkonium chloride (BAK),polyhexamethylene biguanidebiguandide (PHMB), a stabilized oxychlorocomplex, sorbic acid, and combinations thereof. The emulsion can be freeof preservatives. The emulsion has an average droplet size of from about10 nm to 100,000 nm. The emulsion has an average droplet size of 200 nmor less. The emulsion can remain stable for at least 6 months at 25° C.The emulsion can remain stable for at least 12 months at 25° C. Theemulsion can remain stable for at least 24 months at 25° C. The emulsioncan remain stable for at least 6 months at 40° C. The emulsion canremain stable for at least 12 months at 40° C. The emulsion can remainstable for at least 24 months at 40° C. The emulsion can remain stablefor at least 6 months at 50° C. The emulsion can remain stable for atleast 12 months at 50° C. The emulsion can remain stable for at least 24months at 50° C. The emulsion can remain stable for at least 6 months at60° C. The emulsion can remain stable for at least 12 months at 60° C.The emulsion can remain stable for at least 24 months at 60° C. Theemulsion can be formulated as an eyedrop, a cream, a gel, and ointment,a film.

In another aspect, provided herein is an emulsion including about 0.05%to about 1% w/w of a multikinase inhibitor, about 0.1% to about 1% w/wof a poloxyl oil, about 0.05% to about 1% w/w of a lipophilic carrier,about 5% to about 15% w/w of a solubilizer, and water.

In another aspect, provided herein is an emulsion including about 0.005%to about 2% w/w of a multikinase inhibitor, about 0.1% to about 1% w/wof a poloxyl oil, about 0.05% to about 1% w/w of a lipophilic carrier,about 5% to about 15% w/w of a solubilizer, and water.

Implementations can include one or more of the following features. Themultikinase inhibitor can be present in an amount from about 0.1% toabout 0.5% w/w. The polyoxyl oil can be present in an amount from about0.3% to about 0.7% w/w. The lipophilic carrier can be present in anamount from about 0.1% to about 0.5% w/w. The solubilizer can be presentin an amount from about 8% to about 12% w/w.

In another aspect, provided herein is an emulsion including about 0.1%to about 0.5% w/w of a multikinase inhibitor, about 0.3% to about 0.7%w/w of a polyoxyl oil, about 0.1% to about 0.5% w/w of a lipophiliccarrier, about 8% to about 12% w/w of a solubilizer, and water.

Implementations of emulsions provided herein can include one or more ofthe following features. The multikinase inhibitor can be present in anamount of about 0.2% w/w. The polyoxyl oil can be present in an amountof about 0.5% w/w. The lipophilic carrier can be present in an amount ofabout 0.25% w/w. The solubilizer can be present in an amount of about10% w/w.

In another aspect, provided herein is an emulsion including about 0.2%w/w of a multikinase inhibitor, about 0.5% w/w of a polyoxyl oil, about0.25% w/w of a lipophilic carrier, about 10% w/w of a solubilizer,water.

Implementations of emulsions provided herein can include one or more ofthe following features. The multikinase inhibitor can be selected fromthe group consisting of afatinib, amuvatinib, axitinib, cabozantinib,canertinib, cediranib, ceritinib, crenolanib, crizotinib, dabrafenib,dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib,ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib,neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib,quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib,tivantinib, tivozanib, trametinib, vandetanib, vatalanib, vemurafenib,or combinations thereof. The multikinase inhibitor can be selected fromaxitinib, nintedanib, and pazopanib. The multikinase inhibitor can beaxitinib. The multikinase inhibitor can be nintedanib. The multikinaseinhibitor can be pazopanib. The solubilizer can be a cyclicpolysaccharide. The cyclic polysaccharide can be selected from the groupconsisting of cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin,gamma-cyclodextrin, 2-hydroxypropyl-alpha-cyclodextrin,2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin,sulfobutyl ether-beta-cyclodextrin and combinations thereof. Thesolubilizer can include (or can be) 2-hydroxypropyl-beta-cyclodextrin.The polyoxyl oil can be a polyoxyl castor oil. The polyoxyl castor oilcan be polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combinationthereof. The lipophilic carrier can be selected from the groupconsisting of castor oil, squalane, diethylene glycol monoethyl ether,propylene glycol, isostearyl isostearate, isopropyl myristate,dipropylene glycol dimethyl ether, diethylene glycol, dipropyleneglycol, mineral oil, silicone oil, caprylic/capric triglycerides, mediumchain triglycerides and combinations thereof. The lipophilic carrier caninclude (or can be) castor oil. The emulsion can further include asurfactant. In some embodiments, the surfactant can be selected from thegroup consisting of polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 80, polyoxyl-40-stearate, tocopherol, and combinationsthereof. The surfactant can be present in an amount from about 0.05% toabout 5% w/w. The surfactant can be present in an amount from about 0.1%to about 1% w/w. The surfactant can be present in an amount of about0.5w/w. The emulsion can further include an additional constituentselected from the group consisting of a thickener, a buffering agent, atonicity agent, an antioxidant, and combinations thereof. The thickenercan include hydroxypropyl methylcellulose, sodiumcarboxymethylcellulose, or a combination thereof. The thickener can bepresent in an amount from about 0.01% w/w to about 1.0% w/w. Thethickener can be present in an amount from about 0.05% w/w to about 0.5%w/w. The thickener can be present in an amount of about 0.1% w/w. Thebuffering agent can include (or can be) sodium citrate. The bufferingagent can be present in the emulsion in an amount sufficient to maintainthe pH in the range of about 5.5 to about 6.5. The buffering agent canbe present in an amount from about 0.01% w/w to about 1.0% w/w. Thebuffering agent can be present in an amount from about 0.03% w/w toabout 0.06% w/w. The buffering agent can be present in an amount ofabout 0.045% w/w. The antioxidant can include edetate disodium, citricacid, or a combination thereof. The antioxidant can include edetatedisodium, and the edetate disodium can be present in an amount fromabout 0.01% w/w to about 1.0% w/w. The antioxidant can include edetatedisodium, and the edetate disodium can be present in an amount fromabout 0.05% w/w to about 0.5% w/w. The antioxidant can include edetatedisodium, and the edetate disodium can be present in an amount of about0.1% w/w. The antioxidant can include citric acid, and the citric acidcan be present in an amount from about 0.001% to about 0.1% w/w. Theantioxidant can include citric acid, and the citric acid can be presentin an amount from about 0.005% to about 0.05% w/w. The antioxidant caninclude citric acid, and the citric acid can be present in an amount ofabout 0.015%. The tonicity agent can include (or can be) glycerin. Thetonicity agent can be present in an amount from about 0.01% w/w to about1% w/w. The tonicity agent can be present in an amount from about 0.05%w/w to about 0.5% w/w. The tonicity agent can be present in an amount ofabout 0.1% w/w.

In another aspect, provided herein is an emulsion including about 0.2%w/w of a multikinase inhibitor selected from the group consisting ofnintedanib, axitinib, and pazopanib, about 0.5% w/w of a polyoxyl castoroil, about 0.25% w/w of castor oil, about 10% w/w of2-hydroxypropyl-beta-cyclodextrin, and water.

Implementations can include one or more of the following features. Themultikinase

inhibitor can be axitinib. The multikinase inhibitor can be nintedanib.The multikinase inhibitor can be pazopanib. The polyoxyl castor oil canbe polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combinationthereof. The emulsion can further include polysorbate 80 in an amount ofabout 0.5% w/w. The emulsion can further include hydroxypropylmethylcellulose in an amount of about 0.1% w/w. The emulsion can furtherinclude sodium citrate in an amount of about 0.045% w/w. The emulsioncan further include edetate disodium in an amount of about 0.1% w/w. Theemulsion can further include citric acid in an amount of about 0.015%.The emulsion can further include glycerin in an amount of about 0.1%w/w.

In another aspect, provided herein is a method of prolonging theresidence time of a multikinase inhibitor in the ocular surfaceincluding administering any one or more of the emulsions providedherein.

Implementations can include one or more of the following features.Administering can include applying the emulsion to the eye at least onceper day. Administering can include applying the emulsion to the eye atleast twice per day. Administering can include applying the emulsion tothe eye at least three times per day. Administering can include applyingthe emulsion to the eye once per day. Administering can include applyingthe emulsion to the eye twice per day. Administering can includeapplying the emulsion to the eye three times per day.

In another aspect, provided herein is a method of treating an ocularcondition, including administering any one or more of the emulsionsprovided herein to an eye of a subject. The ocular condition can beassociated with angiogenesis.

Implementations can include one or more of the following features. Theocular condition can be selected from the group consisting of hyperemia,neovascularization, pterygium, pinguecula, glaucoma filtration surgeryand minimally invasive glaucoma surgery (MIGS), cornea transplantsurgery with graft rejection, graft versus host disease, dry eyedisease, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell'ssyndrome, Steven Johnson syndrome, viral infection (e.g. HSV-1),bacterial infection, fungal infection, parasitic infection, contact lensinduced neovascularization, ulceration, alkali burns, and stem celldeficiency. The emulsion can remain stable for at least 1 month at 40°C. The emulsion can remain stable for at least 6 months at 40° C. Theemulsion can remain stable for at least 12 months at 40° C. The emulsioncan remain stable for at least 24 months at 40° C. Administering caninclude applying the emulsion to the eye at least once per day.Administering can include applying the emulsion to the eye at leasttwice per day. Administering can include applying the emulsion to theeye at least three times per day. Administering can include applying theemulsion to the eye once per day. Administering can include applying theemulsion to the eye twice per day. Administering can include applyingthe emulsion to the eye three times per day.

In another aspect, provided herein is a method of preparing any of theemulsions described herein, the method including forming a primaryemulsion, reducing the droplet size of the primary emulsion to form ananoemulsion, dissolving a multikinase inhibitor into a solution,combining the nanoemulsion and solution to form a nanoemulsion includingthe multikinase inhibitor; and optionally, filtering the nanoemulsionincluding the multikinase inhibitor.

In another aspect, provided herein is a method of preparing an emulsion,the method including forming a primary emulsion, reducing the dropletsize of the primary emulsion to form a nanoemulsion, dissolving amultikinase inhibitor into a solution, combining the nanoemulsion andsolution to form a nanoemulsion including the multikinase inhibitor, andoptionally, filtering the nanoemulsion including the multikinaseinhibitor.

Implementations of the methods can include one or more of the followingfeatures. Forming the primary emulsion can include high shear mixing.Reducing the droplet size can comprise using a microfluidizer. Filteringcan include using a 0.2-micron filter. The method can further includefilling the filtered nanoemulsion into sterile eye dropper bottles. Thesterile eye dropper bottles are multidose preservative free (MDPF)containers or low density polyethylene (LDPE) unit dose containers. Theprimary emulsion can include a polyoxyl oil, a lipophilic carrier, andwater. The multikinase inhibitor can be selected from afatinib,amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib,crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib,foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib,imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib,palbociclib, pazopanib, ponatinib, quizartinib, regorafenib,ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib, tivozanib,trametinib, vandetanib, vatalanib, vemurafenib, or combinations thereof.The multikinase inhibitor can be selected from axitinib, nintedanib, andpazopanib. The multikinase inhibitor can be axitinib. The multikinaseinhibitor can be nintedanib. The multikinase inhibitor can be pazopanib.The solution can further include a solubilizer. The solubilizer can be acyclic polysaccharide. The cyclic polysaccharide can be selected fromthe group consisting of cyclodextrin, alpha-cyclodextrin,beta-cyclodextrin, gamma-cyclodextrin,2-hydroxypropyl-alpha-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin,2-hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrinand combinations thereof. The polyoxyl oil can be a polyoxyl castor oil.The polyoxyl castor oil can be polyoxyl-40 castor oil, polyoxyl-35castor oil, or a combination thereof. The lipophilic carrier can beselected from the group consisting of castor oil, squalane, diethyleneglycol monoethyl ether, propylene glycol, isostearyl isostearate,isopropyl myristate, dipropylene glycol dimethyl ether, diethyleneglycol, dipropylene glycol, mineral oil, silicone oil, caprylic/caprictriglycerides, medium chain triglycerides and combinations thereof. Theprimary emulsion can further include a surfactant selected from thegroup consisting of polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 80, polyoxyl-40-stearate, tocopherol, and combinationsthereof. The multikinase inhibitor can be nintedanib, the solubilizercan be 2-hydroxypropyl-beta-cyclodextrin, the lipophilic carrier can becastor oil, and the polyoxyl oil can be polyoxyl-35 castor oil, or acombination thereof. The multikinase inhibitor can be present in theprimary emulsion an amount from about 0.001% w/w to about 10.0% w/w. Themultikinase inhibitor can be present in the primary emulsion an amountof about 0.01% to about 1% w/w. The multikinase inhibitor can be presentin the primary emulsion an amount of about 0.1% to about 0.5% w/w. Thelipophilic carrier can be present in the primary emulsion an amount fromabout 0.01% w/w to about 5.0% w/w. The lipophilic carrier can be presentin the primary emulsion in an amount from about 0.05% to about 1% w/w.The lipophilic carrier can be present in the primary emulsion in anamount from about 0.1% to about 0.5% w/w. The polyoxyl oil can bepresent in the primary emulsion in an amount from about 0.01% w/w toabout 10% w/w. The polyoxyl oil can be present in the primary emulsionan amount from about 0.05% to about 1% w/w. The polyoxyl oil can bepresent in the primary emulsion an amount from about 0.1% to about 0.5%w/w. The primary emulsion can further include a solubilizer, wherein thesolubilizer can be present in the primary emulsion in an amount fromabout 1 w/w to about 20% w/w. The solubilizer can be present in theprimary emulsion in an amount from about 5% to about 15% w/w. Thesolubilizer can be present in the primary emulsion in an amount fromabout 8% to about 12% w/w. The primary emulsion can further include anadditional constituent selected from the group consisting of athickener, a buffering agent, a tonicity agent, an antioxidant, andcombinations thereof. The emulsion can be any of the emulsions describedherein.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is an exemplary diagram of the concept of an exemplary dualsynergistic emulsion and solubilizer system utilized in some embodimentsof the compositions described herein.

FIG. 2 is a plot showing reduction of CNV in rabbit by 0.2% nintedanibemulsion or solution according to Example 6.

DETAILED DESCRIPTION

The description herein sets forth details to provide an understanding ofvarious embodiments of the invention and is made with the understandingthat the provided disclosures are an exemplification of the claimedsubject matter without intending to limit the claims to specificembodiments. Accordingly, specific embodiments disclosed herein may becombined with other specific embodiments disclosed herein, includingspecific embodiments under various headings, which are provided forconvenience and organization, but are not to be construed to limit theclaims in any way.

All published documents cited herein are hereby incorporated byreference in their entirety.

As used herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise.

As used herein, and unless otherwise specified, the term “about”, whenused in connection with a numeric value or range of values which isprovided to describe that the value or range of values may deviate to anextent deemed reasonable to one of ordinary skill in the art (e.g., aspecific temperature or temperature range). For example, the term“about”, when used in this context, can, in some embodiments, indicatethat the numeric value or range of values may vary by 5%, 4%, 3%, 2%,1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% of therecited value or range of values. In some embodiments, the numeric valueor range of values may vary by 5%.

Nintedanib, axitinib, and pazopanib are three potent multi-kinaseinhibitors against vascular endothelial growth factor receptor (VEGFR),platelet-derived growth factor receptor (PDGFR) and/or fibroblast growthfactor receptor (FGFR). When formulated as an oral capsule or tablet,nintedanib, axitinib, and pazopanib are effective drug therapies totreat various types of cancers. However, nintedanib, axitinib, andpazopanib are insoluble in water with solubility at room temperatureless than 0.001 mg/mL. These physical and chemical properties may limittheir application and may not allow effective delivery attherapeutically effective concentrations via topical ocularadministration to the target ocular tissues. Surprisingly, it has beenfound that a synergistic effect of an emulsion system, optionallycombined with a solubilizer such as a cyclic oligosaccharide, (e.g.2-hydroxypropyl-beta-cyclodextrin), allows successful formulation ofmultikinase inhibitors such as nintedanib, axitinib or pazopanib at atherapeutically effective concentration with sufficient stability toachieve desirable shelf life. For example, it has unexpectedly beenfound that the emulsion and, optionally, the solubilizer, lead to agreater than additive effect on the solubility of the multikinaseinhibitors, such as nintedanib, axitinib or pazopanib. As shown in FIG.1 , a multikinase inhibitor such as nintedanib, axitinib or pazopanibcould be dissolved into this cyclic oligosaccharide system by beingeffectively trapped into the central cavity of a cyclic oligosaccharide.Although a cyclic oligosaccharide, such as2-hydroxypropyl-beta-cyclodextrin, alone can dissolve a multikinaseinhibitor such as nintedanib, axitinib or pazopanib to a desiredconcentration, the cyclic oligosaccharide-multikinase inhibitor complexmay still dissociate and cause precipitation of the multikinaseinhibitor upon long term storage. Further, it has been surprisingly beenshown that emulsion systems described herein can be dosed lessfrequently (e.g., twice a day) yet demonstrate similar or superioreffectiveness and/or pharmacokinetic properties (e.g., in varioustissues) compared to, for example, a solution formulation (dosed, e.g.,three times a day or more).

To further improve stability, in some embodiments, a multikinaseinhibitor such as nintedanib, axitinib or pazopanib, can form a complexwith a lipophilic carrier system, such as a castor oil lipophiliccarrier, and one or more surfactants such as polysorbate 80 andpolyoxyl-35 castor oil, wherein the multikinase inhibitor wouldeffectively dissolve into the interface of oil droplets of thelipophilic carrier system to form a stable formulation. In someembodiments, the solubility and the stability of the multikinaseinhibitor formulation can be further significantly improved when the oildroplet size is less than or equal to about 200 nm. However, theconcentrations of surfactant in a lipophilic carrier system alone, suchas castor oil with a surfactant such as polysorbate 80 and/orpolyoxyl-35 castor oil, necessary to dissolve nintedanib, axitinib orpazopanib to a desired concentration for topical ocular administrationmay cause irritation to the human eyes. Utilizing the emulsion ornanoemulsion of castor oil, polysorbate 80, polyoxyl-35 castor oil atlow concentrations, optionally in combination with a cyclicoligosaccharide, creates a synergistic effect and can improve theoverall solubility of nintedanib, axitinib or pazopanib to achievetargeted solubility and formulation stability with sufficient shelflife.

In some embodiments, the compositions described herein can remain stablefor at least 6 months, at least 8 months, at least 10 months, at least12 months, at least 15 months, at least 18 months, at least 24 months,or more at room temperate (25° C.). In some embodiments, thecompositions described herein can remain stable for at least 1 month, 2months, 3 months, 4 months, 5 months, or 6 months or more at elevatedtemperatures (e.g., 40° C. to 60° C.). In some embodiments, thecompositions described herein can remain stable for at least 1 month, 2months, 3 months, 4 months, 5 months, or 6 months or more at 40° C. Insome embodiments, the compositions described herein can remain stablefor at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6months or more at 60° C.

Stability can be determined by methods known in the art, including,e.g., observing formula appearance, monitoring for precipitation,monitoring pH changes, monitoring changes in osmolarity, monitoringemulsion phase stability, monitoring emulsion droplet size, and thelike. In some embodiments, the compositions maintain a pH range of fromabout pH 4 to about pH 8 for at least 6 months, at least 8 months, atleast 10 months, at least 12 months, at least 15 months, at least 18months, at least 24 months, or more at room temperate (25° C.). In someembodiments, the compositions maintain a pH range of from about pH 4 toabout pH 8 for at least 1 month, 2 months, 3 months, 4 months, 5 months,or 6 months or more at elevated temperatures (e.g., 40° C. to 60° C.).In some embodiments, the compositions maintain a pH range of from aboutpH 5 to about pH 6 for at least 6 months, at least 8 months, at least 10months, at least 12 months, at least 15 months, at least 18 months, atleast 24 months, or more at room temperate (25° C.). In someembodiments, the compositions maintain a pH range of from about pH 5 toabout pH 6 for at least 1 month, 2 months, 3 months, 4 months, 5 months,or 6 months or more at elevated temperatures (e.g., 40° C. to 60° C.).In some embodiments, the multikinase inhibitor does not precipitate outof the compositions for at least 6 months, at least 8 months, at least10 months, at least 12 months, at least 15 months, at least 18 months,at least 24 months, or more at room temperate (25° C.). In someembodiments, the multikinase inhibitor does not precipitate out of thecompositions for at least 1 month, 2 months, 3 months, 4 months, 5months, or 6 months or more at elevated temperatures (e.g., 40° C. to60° C.).

In some embodiments, the compositions maintain an osmolarity of fromabout 250 mOsm/kg to about 400 mOsm/kg for at least 6 months, at least 8months, at least 10 months, at least 12 months, at least 15 months, atleast 18 months, at least 24 months, or more at room temperate (25° C.).In some embodiments, the compositions maintain an osmolarity of fromabout 250 mOsm/kg to about 400 mOsm/kg for at least 1 month, 2 months, 3months, 4 months, 5 months, or 6 months or more at elevated temperatures(e.g., 40° C. to 60° C.).

In some embodiments, at least 99% of the multikinase inhibitor remainsdissolved in the composition for at least 6 months, at least 8 months,at least 10 months, at least 12 months, at least 15 months, at least 18months, at least 24 months, or more at room temperate (25° C.). In someembodiments, at least 99% of the multikinase inhibitor remains dissolvedin the composition for at least 1 month, 2 months, 3 months, 4 months, 5months, or 6 months or more at elevated temperatures (e.g., 40° C. to60° C.). In some embodiments, at least 99.5% of the multikinaseinhibitor remains dissolved in the composition for at least 6 months, atleast 8 months, at least 10 months, at least 12 months, at least 15months, at least 18 months, at least 24 months, or more at roomtemperate (25° C.). In some embodiments, at least 99.5% of themultikinase inhibitor remains dissolved in the composition for at least1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more atelevated temperatures (e.g., 40° C. to 60° C.).

In some embodiments, 100% of the multikinase inhibitor remains dissolvedin the composition for at least 6 months, at least 8 months, at least 10months, at least 12 months, at least 15 months, at least 18 months, atleast 24 months, or more at room temperate (25° C.). In someembodiments, 100% of the multikinase inhibitor remains dissolved in thecomposition for at least 1 month, 2 months, 3 months, 4 months, 5months, or 6 months or more at elevated temperatures (e.g., 40° C. to60° C.).

This unique formulation system is also well tolerated in humans andanimals and could be an effective treatment option for various ocularconditions, such as diseases affecting the anterior segment of the eye.Furthermore, an emulsion, such as a nanoemulsion, with the addition ofthickening agents, such as sodium carboxymethylcellulose orhydroxypropyl methylcellulose, may increase drug half-life on theaffected ocular surface when administered topically, resulting in anincrease in drug residence time at ocular surface and a decrease indosing frequency while still maintaining pharmaceutically effectivetreatment.

In some embodiments, the disclosure provides an ophthalmic compositioncomprising a therapeutically effective amount of a multikinase inhibitor(e.g., nintedanib or axitinib or pazopanib), optionally wherein saidcombination of an emulsion, such as a nanoemulsion, with a cyclicoligosaccharide, such as 2-hydroxypropyl-beta-cyclodextrin, as asolubilizer, is suitable for topical administration to an eye. In someembodiments, a method is provided for treating an ocular conditionassociated with angiogenesis, such as hyperemia, neovascularization,pterygium, pinguecula, glaucoma filtration surgery and minimallyinvasive glaucoma surgery (MIGS), cornea transplant surgery with graftrejection, graft versus host disease, dry eye disease, atopicconjunctivitis, rosacea, ocular pemphigoid, Lyell's syndrome, StevenJohnson syndrome, viral infection (e.g. HSV-1), bacterial infection,fungal infection, parasitic infection, contact lens inducedneovascularization, ulceration, alkali burns, stem cell deficiency, isalso disclosed herein, and wherein at least one symptom of the ocularcondition is alleviated, regressed, or halted. As used herein, unlessotherwise specified, the term “nintedanib or axitinib or pazopanib”include their free base, salts, analogues, esters, and combinationsthereof.

Furthermore, the compositions disclosed herein could comprise compoundswith a similar pharmacological profile and physical and chemicalproperties of multikinase inhibitors, such as afatinib, amuvatinib,cabozantinib, canertinib, cediranib, ceritinib, crenolanib, crizotinib,dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib,golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib,lenvatinib, neratinib, nilotinib, palbociclib, ponatinib, quizartinib,regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib,tivozanib, trametinib, vandetanib, vatalanib, and vemurafenib.

In some embodiments, the compositions described herein can be useful fortreating one or more ocular conditions in an affected eye of a subject.Methods are provided herein, comprising administering a compositiondescribed herein to an affected eye of a subject. In some embodiments,the ocular condition can be any condition of an eye, resulting from anangiogenesis in the anterior segment or posterior segment of an eye. Thesubject to be treated can be of any age, or gender. In some embodiments,the subject can be human. In some embodiments, the subject can be anon-human mammal.

In some embodiments, a pharmaceutical composition disclosed herein mayinclude a “therapeutically effective amount” of an agent describedherein. Such effective amounts can be determined based on the effect ofthe administered agent, or the combinatorial effect of agents if morethan one agent is used. A therapeutically effective amount of an agentmay also vary according to factors such as the disease state, age, sex,and weight of the individual, and the ability of the compound to elicita desired response in the individual, e.g., amelioration of at least onedisorder parameter or amelioration of at least one symptom of thedisorder. A therapeutically effective amount is also one in which anytoxic or detrimental effects of the composition are outweighed by thetherapeutically beneficial effects. As used herein, a dosage isconsidered effective if it ameliorates, prevents, reduces, or eliminatesthe symptoms associated with the ocular condition to be treated.

In some embodiments, the multikinase inhibitor, such as nintedanib oraxitinib or pazopanib, can be present in the ophthalmic compositionsdescribed herein in an amount from about 0.001% to about 10.0% (w/w). Insome embodiments, the multikinase inhibitor is present in an amount offrom about 0.005% to about 2% (w/w), from about 0.001% to about 1%(w/w), from about 0.001% to about 0.005% (w/w), from about 0.005% toabout 0.01% (w/w), from about 0.01% to about 0.05% (w/w), from about0.05% to about 0.1% (w/w), from about 0.01% to about 1% (w/w), fromabout 0.05% to about 0.5%, from about 0.01% to about 0.8% (w/w), fromabout 0.3% to about 0.7% (w/w), from about 0.4% to about 0.6% (w/w),from about 0.1% to about 10% (w/w), from about 0.1% to about 0.5% (w/w),from about 0.2% to about 8% (w/w), from about 0.4% to about 5% (w/w), orfrom about 0.4% to about 2% (w/w). In some embodiments the multikinaseinhibitor is present at a concentration of about 0.5% (w/w). In someembodiments, the multikinase inhibitor is preset at a concentration ofabout 0.2% (w/w). In some embodiments, at least 99% of the multikinaseinhibitor is dissolved in the composition. In some embodiments, at least99.5% of the multikinase inhibitor is dissolved in the composition. Insome embodiments, 100% of the multikinase inhibitor is dissolved in thecomposition.

In some embodiments, the disclosed compositions can be emulsions,solutions, suspensions, gels, ointments, occlusive films, or a sustainedrelease formulation and they can be preserved or non-preservedformulations. In some embodiments, the disclosed compositions can beemulsions. In some embodiments, the disclosed compositions can benanoemulsions. An emulsion can have any appropriate droplet size (e.g.,about 10 nm to about 10,000 nm, about 100 nm to about 500 nm, less thanabout 500 nm, less than about 400 nm, less than about 300 nm, less thanabout 200 nm, or less than about 100 nm). The compositions can beformulated as eye drops, creams, ointments, films, gels and implants(e.g., a sustained release implant) that can be applied to an eye. Theformulations can be administered to an eye of a subject in need thereof.

Listed in Table 1 are non-limiting examples of possible formulationingredients and their exemplary concentrations.

TABLE 1 Composition Function Ingredient (% w/w) Active nintedanib0.01-10.0 axitinib 0.001-10.0  pazopanib 0.01-10.0 Thickener/Viscositycarbomer, sodium   0-3.0 Agent carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, Zanthangum Antioxidant Agent edetate disodium,   0-1.0 dibutylhydroxytoluene,citric acid, sodium metabisulfite, tocopherol acetate Surfactantpolysorbate 20, polysorbate 40,    0-10.0 polysorbate 60, polysorbate80, polyoxyl-40-stearate, polyoxyl- 35 castor oil, polyoxyl-40 castoroil, tocopherol and other polymeric emulsifiers Lipophilic Vehiclecastor oil, squalene, isostearyl    0-10.0 isostearate, isopropylmyristate, mineral oil, silicone oil, medium chain triglyceridesBuffering Agent sodium citrate dihydrate,   0-2.0 sodium citrate boricacid, monosodium phosphate monohydrate, sodium phosphate dibasicheptahydrate, sodium phosphate monobasic monohydrate Tonicity Agentglycerin, erythritol, mannitol,   0-3.0 potassium chloride, sodiumchloride Solubilizer/Solubility cyclodextrin, alpha-cyclodextrin,   0-20.0 Enhancing beta-cyclodextrin, gamma- Agent cyclodextrin,2-hydroxypropyl- beta-cyclodextrin, 2- hydroxypropyl-alpha-cyclodextrin, 2-hydroxypropyl- gamma-cyclodextrin, sulfobutylether-beta-cyclodextrin Preservative benzalkonium chloride, Purite,  0-2.0 sorbic acid, PHMB and other ophthalmic preservatives HydrophilicVehicle water    0-99.0

In some embodiments, the composition can comprise a lipophilic carriersuch as, castor oil, squalane, diethylene glycol monoethyl ether,propylene glycol, isostearyl isostearate, isopropyl myristate,dipropylene glycol dimethyl ether, diethylene glycol, dipropyleneglycol, mineral oil, silicone oil, caprylic/capric triglycerides, mediumchain triglycerides, and combinations thereof. In some embodiments, thelipophilic carrier can include castor oil In some embodiments, thelipophilic vehicle can be present in an amount of from about 0% to about10% of the composition by weight (e.g., about 0.001% to about 10% (w/w),about 0.01% to about 5.0% (w/w), about 0.05% to about 1.0% (w/w), orabout 0.1% to about 0.5% (w/w)). In some embodiments, the lipophiliccarrier can be present in an amount of about 0.25% (w/w).

In some embodiments, the composition can comprise one or moresurfactants, such as polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 80, polyoxyl-40-stearate, polyoxyl-35 castor oil,polyoxyl-40 castor oil, tocopherol, other polymeric emulsifiers, andcombinations thereof. In some embodiments, the composition can include asurfactant that is a polyoxyl oil, such as a polyoxyl castor oil (e.g.,polyoxyl-35 castor oil, polyoxyl-40 castor oil, or a combinationthereof) (e.g., a CREMOPHOR® or a KOLLIPHOR®). In some such embodiments,the composition can further include one or more additional surfactantsthat are not a polyoxyl oil (e.g., a polysorbate, such as polysorbate20, polysorbate 40, polysorbate 60, polysorbate 80, or a combinationthereof). In some embodiments, a surfactant can be present in an amountof from about 0% to about 10% by weight of the composition (e.g., about0.001% to about 10% (w/w), about 0.05% to about 5% (w/w), about 0.01% toabout 1.0% (w/w), or about 0.1% to about 0.5% (w/w)). In someembodiments, a surfactant can be present in an amount of about 0.5%(w/w). In some embodiments, a polyoxyl oil can be present in an amountof from about 0% to about 10% by weight of the composition (e.g., about0.001% to about 10% (w/w), about 0.05% to about 5% (w/w), about 0.01% toabout 1.0% (w/w), or about 0.1% to about 0.5% (w/w)). In someembodiments, a polyoxyl oil can be present in an amount of about 0.5%(w/w). In some such embodiments, a second surfactant can be present inan amount of from about 0% to about 10% by weight of the composition(e.g., about 0.001% to about 10% (w/w), about 0.05% to about 5% (w/w),about 0.01% to about 1.0% (w/w), or about 0.1% to about 0.5% (w/w)). Insome embodiments, a second surfactant can be present in an amount ofabout 0.5% (w/w).

In some embodiments, the composition can comprise a tonicity agent, suchas sodium chloride, glycerin, mannitol, potassium chloride, erythritol,and combinations thereof in an amount sufficient to maintain theosmolarity in the range of 250 to 400 mOsm/kg (e.g., about 250 to about300 mOsm/kg or about 300 to about 400 mOsm/kg). In some embodiments, atonicity agent can include glycerin. In some embodiments, a tonicityagent can be present in an amount of from about 0 to about 10% by weightof the composition (e.g., about 0% to about 3%, about 0.1% to about 10%(w/w), about 0.01% to about 1% (w/w), or about 0.05% to about 0.5%(w/w)). In some embodiments, a tonicity agent can be present in anamount of about 0.1% (w/w).

In some embodiments, the composition can comprise an antioxidant, suchas edetate disodium, dibutylhydroxytoluene, citric acid, sodiummetabisulfite, tocopherol acetate, and combinations thereof. In someembodiments, an antioxidant can be selected from the group consisting ofedetate disodium, citric acid, and combinations thereof. In someembodiments, the antioxidant can be present in an amount of from about 0to about 1% by weight of the composition (e.g., about 0.01% to about1.0% (w/w) or about 0.05% to about 0.5% (w/w). In some embodiments, theantioxidant can be present in an amount of about 0.115% (w/w). In someembodiments, the antioxidant can comprise edetate disodium, and theedetate disodium can be present in an amount of about 0.01% to about1.0% (w/w), about 0.05% to about 0.5% (w/w), or about 0.1% (w/w). Insome embodiments, the antioxidant can comprise citric acid, and thecitric acid can be present in an amount of about 0.001% to about 0.1%(w/w), 0.005% to about 0.05% (w/w), or about 0.015% (w/w).

In some embodiments, the composition can include one or more bufferingagents. Suitable buffering agents include, but are not limited to,phosphates, citrates, acetates, borates, and combinations thereof. Insome embodiments, the buffering agent can be selected from the groupconsisting of sodium citrate dihydrate, sodium citrate, sodium phosphatemonobasic monohydrate, monosodium phosphate monohydrate, sodiumphosphate dibasic heptahydrate, boric acid, and combinations thereof. Insome embodiments, the buffering agent can be selected from the groupconsisting of sodium citrate dihyrdrate, sodium citrate, and acombination thereof. In some embodiments, the buffering agent can beselected from the group consisting of sodium citrate dihyrdrate, sodiumcitrate, or a combination thereof. The amount of buffer componentemployed is sufficient to maintain the pH of the composition in a rangeof about 4 to about 8 (e.g., about 5.0 to about 7.0, or about 5.5 toabout 6.5) throughout product shelf life. In certain embodiments, thebuffer is present in an amount of about 0 to about 2.0% by weight of thecomposition (e.g., about 0.01% to about 1.0% (w/w) or about 0.03% toabout 0.06% (w/w)). In some embodiments, the buffer is present in anamount of about 0.045% (w/w).

In some embodiments, the composition can include a thickener orviscosity agent. In some embodiments, the viscosity agent can beselected from carbomer, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl cellulose (e.g., a HPMC with an averagecontent of methoxyl group of about 29% and an average content ofhydroxypropyl group of about 10%), polyvinyl alcohol, xanthan gum, andcombinations thereof. In some embodiments, the thickener can behydroxypropyl methylcellulose, sodium carboxymethylcellulose, or acombination thereof. In some embodiments, the viscosity agent can bepresent in an amount of about 0% to about 3% by weight of thecomposition (e.g., about 0.01% to about 1.0% (w/w) or about 0.05% toabout 0.5% (w/w)). In some embodiments, the thickener can be present inan amount of about 0.1% (w/w).

In some embodiments, the composition can include a solubilizer orsolubility enhancing agent. In some embodiments, the solubilizer can bea cyclic oligosaccharide. In some embodiments, the solubilizer orsolubility enhancing agent can be selected from cyclodextrin,alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin,2-hydroxypropyl-alpha-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin(sometimes also called HPBCD or HP-beta-CD),2-hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrinand combinations thereof. In some embodiments, the solubilizer caninclude 2-hydroxypropl-beta-cyclodextrin. In some embodiments, thesolubilizer or solubility enhancing agent can be present in an amount ofabout 0% to about 20% by weight of the composition (e.g., about 1% toabout 20% (w/w), about 5% to about 15% (w/w), or about 8% to about 12%(w/w). In some embodiments, the solubilizer or solubility enhancingagent can be present in an amount of about 10% (w/w).

In some embodiments, the composition can be administered topically inthe form of an eye drop, cream, ointment, film, suspension, gel or thelike. In some embodiments, the composition can be administered to asingle eye or to both eyes of a subject.

The compositions of or used in, the present disclosure may include oneor more other components in amounts effective to provide one or moreuseful properties and/or benefits. For example, although the presentcompositions may be substantially free of added preservative components,in other embodiments, the present compositions include effective amountsof preservative components. Examples of such preservative componentsinclude, without limitation, a stabilized oxychloro complex (e.g.,PURITE®), quaternary ammonium preservatives such as benzalkoniumchloride (“BAC or “BAK”), sorbic acid, and polyoxamer;biguanidebigunanide preservatives such as polyhexamethylenebiguanidebiguandide (PHMB); methyl and ethyl parabens; hexetidine;chlorite components, such as stabilized chlorine dioxide, metalchlorites and the like; other ophthalmically acceptable preservativesand mixtures thereof. The concentration of the preservative component,if any, in the present compositions is a concentration effective topreserve the composition and is often and generally used in a range ofabout 0% to about 2.0% by volume of the composition.

Typically, water makes up the balance of compositions described herein.

In some embodiments provided herein are compositions with varyingcombinations of ingredients. Exemplary compositions are shown in TableA.

TABLE A Exemplary Exemplary Exemplary Exemplary Amount A1 Amount A2Amount A3 Component component (w/w) (w/w) (w/w) Multikinase Nintedanib,about About About inhibitor axitinib, or 0.005%- 0.1%- 0.2% pazopanibabout 2% about 0.5% Polyoxyl Polyoxy1-35 About About About oil castoroil 0.1%- 0.3%- 0.5% about 1% about 0.7% Lipophilic Castor oil AboutAbout About carrier 0.05%- 0.1%- 0.25% about 1% about 0.5% Solubilizer2- About About hydroxypropyl- 5%- About 8%- 10% beta- about 15% about12% cyclodextrin

Additional components may be present in the compositions providedherein. Exemplary additional components are shown in Table B. Eachcombination of Table A and Table B is explicitly contemplated (e.g.,A1B1, A2B1, A3B1, A1B2, A2B2, A3B2, A1B3, A2B3, and A3B3).

TABLE B Exemplary Exemplary Exemplary Exemplary Amount B1 Amount B2Amount B3 Component component (w/w) (w/w) (w/w) Surfactant Polysorbate80 About About About 0.05%- 0.1% to 0.5% about 5% about 1% ThickenerHydroxypropyl About About About methylcellulose 0.01%- 0.05%- 0.1% about1.0% about 0.5% Buffering Sodium citrate About About About Agent 0.01%-0.03%- 0.045% about 1.0% 0.06% Antioxidant Edetate About About Aboutdisodium 0.01%- 0.05%- 0.115% and/or about 1.0% about 0.5% citric acidTonicity Glycerin About About About agent 0.01%- 0.05%- 0.1% about 1%about 0.5%

Also provided herein are methods of preparing compositions (e.g.,emulsions). In some embodiments, the compositions can be any of thecompositions described herein.

In some embodiments, the methods can include dissolving a multikinaseinhibitor into a primary emulsion, reducing the droplet size of theprimary emulsion to form a nanoemulsion, and filtering the nanoemulsion.In some embodiments, dissolving the multikinase inhibitor can includehigh shear mixing. In some embodiments, the methods can include forminga primary emulsion, reducing the droplet size of the primary emulsion toform a nanoemulsion, dissolving a multikinase inhibitor into a solution,combining the nanoemulsion and solution to form a nanoemulsioncomprising the multikinase inhibitor, and optionally, filtering thenanoemulsion comprising the multikinase inhibitor. In some embodiments,dissolving a multikinase inhibitor into a solution can includedissolving a multikinase inhibitor into a solution including asolubilizer (e.g., any of the solubilizers described herein). In someembodiments, the solution can further include a buffer (e.g., sodiumcitrate), an antioxidant (e.g., citric acid and/or trisodium EDTA), athickener (e.g., HPMC), or a combination thereof.

In some embodiments, reducing the droplet size can include using amicrofluidizer. Filtering the nanoemulsion can be performed using afilter of any appropriate size (e.g., a 0.2-micron filter). In someembodiments, the method can include filling the filtered nanoemulsioninto sterile eye dropper bottles. Non-limiting examples of sterile eyedropper bottles include multidose preservative free (MDPF) containers orlow density polyethylene (LDPE) unit dose containers. In someembodiments a primary emulsion can include a polyoxyl oil, a lipophiliccarrier, and water. In some embodiments, a primary emulsion can furtherinclude a surfactant. In some embodiments, a primary emulsion canfurther include a solubilizer. In some embodiments, a primary emulsioncan include one or more of a thickener, a buffering agent, a tonicityagent, an antioxidant, and combinations thereof.

The frequency, duration, and dosage of the administration are determinedby the prescribing physician. The dosage can vary depending on thedosage formulation. Frequency of administration can be one or more timesdaily (such as once, twice, three, or four or more times daily),bi-weekly (such as every two weeks or twice a week), and/or monthly.Duration of administration can continue until the ocular condition to betreated is resolved, that is, until one or more symptoms of the ocularcondition are ameliorated, reduced, or eliminated. In some embodiments,a composition described herein can be administered for hours, days,weeks, months, or years.

A symptom is considered to be alleviated or ameliorated if it isprevented, reduced or eliminated. A symptom is prevented in a patientthat typically experiences a particular symptom with the ocularcondition and the patient does not experience the onset of the symptomfollowing administration of the disclosed composition. A reduction of asymptom is considered achieved if there is a 5%, 10%, 20%, 50%, 75%, 90%or more reduction in the severity or duration of one or more symptomsassociated with the ocular condition in a patient. An elimination of oneor more symptoms associated with the ocular condition is achieved whenit ceases to be present or substantially present in a patient. In someembodiments an elimination of one or more symptoms associated with theocular condition is achieved when 90% or more of one or more symptomscease to be present.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements. The recitations of numericalranges by endpoints include all numbers subsumed within that range(e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention are to be construed to cover both the singularand the plural, unless otherwise indicated herein or clearlycontradicted by context. Recitation of ranges of values herein is merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range.

Unless otherwise indicated herein, each individual value is incorporatedinto the specification as if it were individually recited herein. Allmethods described herein can be performed in any suitable order unlessotherwise indicated herein or otherwise clearly contradicted by context.The use of any and all examples, or exemplary language (e.g., “such as”)provided herein is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention otherwiseclaimed. No language in the specification should be construed asindicating any non-claimed element essential to the practice of theinvention. Groupings of alternative elements or embodiments of theinvention disclosed herein are not to be construed as limitations. Eachgroup member may be referred to and claimed individually or in anycombination with other members of the group or other elements foundherein. It is anticipated that one or more members of a group may beincluded in, or deleted from, a group for reasons of convenience and/orpatentability.

Certain embodiments of this invention are described herein. Of course,variations on these described embodiments will become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventor expects skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

The present invention is not limited to that precisely as shown anddescribed. Specific embodiments disclosed herein may be further limitedin the claims using “consisting of” or “consisting essentially of”language. When used in the claims, whether as filed or added peramendment, the transition term “consisting of” excludes any element,step, or ingredient not specified in the claims. The transition term“consisting essentially of” limits the scope of a claim to the specifiedmaterials or steps and those that do not materially affect the basic andnovel characteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

It is to be understood that the embodiments of the invention disclosedherein are illustrative of the principles of the present invention.Other modifications that may be employed are within the scope of theinvention. Thus, by way of example, but not of limitation, alternativeconfigurations of the present invention may be utilized in accordancewith the teachings herein.

EXEMPLARY EMBODIMENTS

Embodiment 1 is an emulsion comprising:

-   -   a therapeutically effective amount of a multikinase inhibitor;    -   a polyoxyl oil;    -   a lipophilic carrier;    -   and    -   water.

Embodiment 2 is the emulsion of embodiment 1, wherein the emulsion is ananoemulsion.

Embodiment 3 is the emulsion of any one of embodiments 1 to 2, whereinthe multikinase inhibitor is selected from afatinib, amuvatinib,axitinib, cabozantinib, canertinib, cediranib, ceritinib, crenolanib,crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib,gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib,lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib,pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib,sunitinib, tandutinib, tivantinib, tivozanib, trametinib, vandetanib,vatalanib, vemurafenib, or combinations thereof.

Embodiment 4 is the emulsion of embodiment 3, wherein the multikinaseinhibitor is selected from axitinib, nintedanib, and pazopanib.

Embodiment 5 is the emulsion of embodiment 3, wherein the multikinaseinhibitor is axitinib.

Embodiment 6 is the emulsion of embodiment 3, wherein the multikinaseinhibitor is nintedanib.

Embodiment 7 is the emulsion of embodiment 3, wherein the multikinaseinhibitor is pazopanib.

Embodiment 8 is the emulsion of any one of embodiments 1 to 7, furthercomprising a solubilizer.

Embodiment 9 is the emulsion of any one of embodiments 1 to 8, whereinthe solubilizer is a cyclic polysaccharide.

Embodiment 10 is the emulsion of embodiment 4, wherein the cyclicpolysaccharide is selected from the group consisting of cyclodextrin,alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin,2-hydroxypropyl-alpha-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin,2-hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrinand combinations thereof.

Embodiment 11 is the emulsion of any one of embodiments 1 to 10, whereinthe polyoxyl oil is a polyoxyl castor oil.

Embodiment 12 is the emulsion embodiment 11, wherein the polyoxyl castoroil is polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combinationthereof.

Embodiment 13 is the emulsion of any one of embodiments 1 to 12, whereinthe lipophilic carrier is selected from the group consisting of castoroil, squalane, diethylene glycol monoethyl ether, propylene glycol,isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethylether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil,caprylic/capric triglycerides, medium chain triglycerides andcombinations thereof.

Embodiment 14 is the emulsion of any one of embodiments 1 to 13, furthercomprising a surfactant selected from the group consisting ofpolysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxyl-40-stearate, tocopherol, and combinations thereof.

Embodiment 15 is the emulsion of embodiment 1, wherein the multikinaseinhibitor is nintedanib, the solubilizer is2-hydroxypropyl-beta-cyclodextrin, the lipophilic carrier is castor oil,and the polyoxyl oil is polyoxyl-35 castor oil, or a combinationthereof.

Embodiment 16 is the emulsion of any one of embodiments 1 to 15, whereinthe multikinase inhibitor is present in an amount from about 0.001% w/wto about 10.0% w/w.

Embodiment 17 is the emulsion of embodiment 16, wherein the multikinaseinhibitor is present in an amount of about 0.01% to about 1% w/w.

Embodiment 18 is the emulsion of embodiment 16, wherein the multikinaseinhibitor is present in an amount of about 0.1% to about 0.5% w/w.

Embodiment 19 is the emulsion of any one of embodiments 1 to 14, whereinthe multikinase inhibitor is nintedanib and the nintedanib is present inan amount from about 0.01% w/w to about 10.0% w/w.

Embodiment 20 is the emulsion of embodiment 19, wherein the nintedanibis present in an amount from about 0.01% to about 1% w/w.

Embodiment 21 is the emulsion of embodiment 19, wherein the nintedanibis present in an amount from about 0.1% to about 0.5% w/w.

Embodiment 22 is the emulsion of any one of embodiments 1 to 14, whereinthe multikinase inhibitor is axitinib, and the axitinib is present inthe emulsion in an amount from about 0.001% w/w to about 10.0% w/w.

Embodiment 23 is the emulsion of embodiment 22, wherein the axitinib ispresent in an amount from about 0.01% to about 1% w/w.

Embodiment 24 is the emulsion of embodiment 22, wherein the axitinib ispresent in an amount from about 0.05% to about 0.5% w/w.

Embodiment 25 is the emulsion of any one of embodiments 1 to 14, whereinthe multikinase inhibitor is pazopanib, and the pazopanib is present inan amount from about 0.01% w/w to about 10.0% w/w.

Embodiment 26 is the emulsion of embodiment 25, wherein the pazopanib ispresent in an amount from about 0.01% to about 1% w/w.

Embodiment 27 is the emulsion of embodiment 25, wherein the pazopanib ispresent in an amount from about 0.1% to about 0.5% w/w.

Embodiment 28 is the emulsion of any one of embodiments 1 to 27, whereinthe lipophilic carrier is present in an amount from about 0.01% w/w toabout 5.0 w/w.

Embodiment 29 is the emulsion of embodiment 28, wherein the lipophiliccarrier is present in an amount from about 0.05% to about 1% w/w.

Embodiment 30 is the emulsion of embodiment 28, wherein the lipophiliccarrier is present in an amount from about 0.1% to about 0.5% w/w.

Embodiment 31 is the emulsion of any one of embodiments 1 to 30, whereinthe polyoxyl oil is present in an amount from about 0.01% w/w to about10% w/w.

Embodiment 32 is the emulsion of embodiment 31, wherein the polyoxyl oilis present in an amount from about 0.05% to about 1% w/w.

Embodiment 33 is the emulsion of embodiment 31, wherein the polyoxyl oilis present in an amount from about 0.1% to about 0.5% w/w.

Embodiment 34 is the emulsion of any one of embodiments 1 to 33, furthercomprising a solubilizer, wherein the solubilizer is present in theemulsion in an amount from about 1 w/w to about 20% w/w.

Embodiment 35 is the emulsion of embodiment 34, wherein the solubilizeris present in an amount from about 5% to about 15% w/w.

Embodiment 36 is the emulsion of embodiment 34, wherein the solubilizeris present in an amount from about 8% to about 12% w/w.

Embodiment 37 is the emulsion of any one of embodiments 1 to 36, furthercomprising an additional constituent selected from the group consistingof a thickener, a buffering agent, a tonicity agent, an antioxidant, andcombinations thereof.

Embodiment 38 is the emulsion of embodiment 37, wherein the thickener isselected from the group consisting of carbomer, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinylalcohol, xanthan gum, and combinations thereof.

Embodiment 39 is the emulsion of embodiment 38, wherein the thickener ishydroxypropyl methylcellulose, sodium carboxymethylcellulose, or acombination thereof.

Embodiment 40 is the emulsion of any one of embodiments 37-39, whereinthe thickener is present in an amount from about 0.01% w/w to about 1.0%w/w.

Embodiment 41 is the emulsion of any one of embodiments 37-39, whereinthe thickener is present in an amount from about 0.05% w/w to about 0.5%w/w.

Embodiment 42 is the emulsion any one of embodiments 37-41, wherein thebuffering agent is selected from the group consisting of phosphates,citrates, acetates, borates, and combinations thereof.

Embodiment 43 is the emulsion of any one of embodiments 37-42, whereinthe buffering agent is selected from the group consisting of sodiumcitrate dihydrate, sodium citrate, sodium phosphate monobasicmonohydrate, monosodium phosphate monohydrate, sodium phosphate dibasicheptahydrate, boric acid, and combinations thereof.

Embodiment 44 is the emulsion of any one of embodiments 37-43, whereinthe buffering agent is selected from the group consisting of sodiumcitrate dihyrdrate, sodium citrate, or a combination thereof.

Embodiment 45 is the emulsion of any one of embodiments 37-44, whereinthe buffering agent is present in the emulsion in an amount sufficientto maintain the pH in the range of 4.0 to 8.0.

Embodiment 46 is the emulsion of any one of embodiments 37-44, whereinthe buffering agent is present in the emulsion in an amount sufficientto maintain the pH in the range of about 5.5 to about 6.5.

Embodiment 47 is the emulsion of any one of embodiments 37-46, whereinthe buffering agent is present in an amount of about 0.01% w/w to about1.0% w/w.

Embodiment 48 is the emulsion of any one of embodiments 37-46, whereinthe buffering agent is present in an amount of about 0.03% w/w to about0.06% w/w.

Embodiment 49 is the emulsion any one of embodiments 37-48, wherein theantioxidant is selected from the group consisting of edetate disodium,dibutylhydroxytoluene, citric acid, sodium metabisulfite, tocopherolacetate, and combinations thereof.

Embodiment 50 is the emulsion of any one of embodiments 37-48, whereinthe antioxidant is selected from the group consisting of edetatedisodium, citric acid, and combinations thereof.

Embodiment 51 is the emulsion of any one of embodiments 37-50, whereinthe antioxidant is present in an amount from about 0.01% to about 1.0%w/w.

Embodiment 52 is the emulsion of any one of embodiments 37-50, whereinthe antioxidant is present in an amount from about 0.05% to about 0.5%w/w.

Embodiment 53 is the emulsion of any one of embodiments 37-52, whereinthe antioxidant comprises edetate disodium, and the edetate disodium ispresent in an amount from about 0.01% w/w to about 1.0% w/w.

Embodiment 54 is the emulsion of any one of embodiments 37-52, whereinthe antioxidant comprises edetate disodium, and the edetate disodium ispresent in an amount from about 0.05% w/w to about 0.5 w/w.

Embodiment 55 is the emulsion of any one of embodiments 37-54, whereinthe antioxidant comprises citric acid, and the citric acid is present inan amount from about 0.001% to about 0.1% w/w.

Embodiment 56 is the emulsion of any one of embodiments 37-54, whereinthe antioxidant comprises citric acid, and the citric acid is present inan amount from about 0.005% to about 0.05% w/w.

Embodiment 57 is the emulsion of any one of embodiments 37-56, whereinthe tonicity agent is selected from the group consisting of sodiumchloride, glycerin, mannitol, potassium chloride, erythritol, andcombinations thereof.

Embodiment 58 is the emulsion of any one of embodiments 37-56, whereinthe tonicity agent is glycerin.

Embodiment 59 is the emulsion of any one of embodiments 37-58, whereinthe tonicity agent is present in an amount from about 0.1% w/w to about10% w/w.

Embodiment 60 is the emulsion of any one of embodiments 37-58, whereinthe tonicity agent is present in an amount from about 0.01% w/w to about1% w/w.

Embodiment 61 is the emulsion of any one of embodiments 37-58, whereinthe tonicity agent is present in an amount from about 0.05% w/w to about0.5% w/w.

Embodiment 62 is the emulsion of any one of embodiments 37 to 61,wherein the tonicity agent is present in an amount sufficient tomaintain the osmolarity in the range of 250 to 400 mOsm/kg.

Embodiment 63 is the emulsion of any one of embodiments 1-62, whereinthe emulsion further comprises a preservative.

Embodiment 64 is the emulsoion of embodiment 63, wherein thepreservative is selected from the group consisting of benzalkoniumchloride (BAK), polyhexamethylene biguanidebiguandide (PHMB), astabilized oxychloro complex, sorbic acid, and combinations thereof.

Embodiment 65 is the emulsion of any one of embodiments 1-64, whereinthe emulsion is free of preservatives.

Embodiment 66 is the emulsion of any one of embodiments 1-65, whereinthe emulsion has an average droplet size of from about 10 nm to 100,000nm.

Embodiment 67 is the emulsion of any one of embodiments 1-66, whereinthe emulsion has an average droplet size of 200 nm or less.

Embodiment 68 is the emulsion of any one of embodiments 1-67, whereinthe emulsion remains stable for at least 6 months at 25° C.

Embodiment 69 is the emulsion of any one of embodiments 1-68, whereinthe emulsion remains stable for at least 12 months at 25° C.

Embodiment 70 is the emulsion of any one of embodiments 1-69, whereinthe emulsion remains stable for at least 24 months at 25° C.

Embodiment 71 is the emulsion of any one of embodiments 1-70, whereinthe emulsion is formulated as an eyedrop, a cream, a gel, and ointment,a film.

Embodiment 72 is an emulsion comprising:

-   -   about 0.005% to about 2% w/w of a multikinase inhibitor;    -   about 0.1% to about 1% w/w of a poloxyl oil;    -   about 0.05% to about 1% w/w of a lipophilic carrier;    -   about 5% to about 15% w/w of a solubilizer; and    -   water.

Embodiment 73 is the emulsion of embodiment 72, wherein the multikinaseinhibitor is present in an amount from about 0.1% to about 0.5% w/w.

Embodiment 74 is the emulsion of any one of embodiments 72-73, whereinthe polyoxyl oil is present in an amount from about 0.3% to about 0.7%w/w.

Embodiment 75 is the emulsion of any one of embodiments 72-74, whereinthe lipophilic carrier is present in an amount from about 0.1% to about0.5% w/w.

Embodiment 76 is the emulsion of any one of embodiments 72-75, whereinthe solubilizer is present in an amount from about 8% to about 12% w/w.

Embodiment 77 is an emulsion comprising:

-   -   about 0.1% to about 0.5% w/w of a multikinase inhibitor;    -   about 0.3% to about 0.7% w/w of a polyoxyl oil;    -   about 0.1% to about 0.5% w/w of a lipophilic carrier;    -   about 8% to about 12% w/w of a solubilizer; and    -   water.

Embodiment 78 is the emulsion of any one of embodiments 72-77, whereinthe multikinase inhibitor is present in an amount of about 0.2% w/w.

Embodiment 79 is the emulsion of any one of embodiments 72-78, whereinthe polyoxyl oil is present in an amount of about 0.5% w/w.

Embodiment 80 is the emulsion of any one of embodiments 72-79, whereinthe lipophilic carrier is present in an amount of about 0.25% w/w.

Embodiment 81 is the emulsion of any one of embodiments 72-80, whereinthe solubilizer is present in an amount of about 10% w/w.

Embodiment 82 is an emulsion comprising:

-   -   about 0.2% w/w of a multikinase inhibitor;    -   about 0.5% w/w of a polyoxyl oil;    -   about 0.25% w/w of a lipophilic carrier;    -   about 10% w/w of a solubilizer; and    -   water.

Embodiment 83 is the emulsion of any one of embodiments 72-83, whereinthe multikinase inhibitor is selected from the group consisting ofafatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib,ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib,erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib,idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib,nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib,ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib, tivozanib,trametinib, vandetanib, vatalanib, vemurafenib, or combinations thereof.

Embodiment 84 is the emulsion of any one of embodiments 72-83, whereinthe multikinase inhibitor is selected from axitinib, nintedanib, andpazopanib.

Embodiment 85 is the emulsion of any one of embodiments 72-83, whereinthe multikinase inhibitor is axitinib.

Embodiment 86 is the emulsion of any one of embodiments 72-83, whereinthe multikinase inhibitor is nintedanib.

Embodiment 87 is the emulsion of any one of embodiments 72-83, whereinthe multikinase inhibitor is pazopanib.

Embodiment 88 is the emulsion of any one of embodiments 72-87, whereinthe solubilizer is a cyclic polysaccharide.

Embodiment 89 is the emulsion of embodiment 88, wherein the cyclicpolysaccharide is selected from the group consisting of cyclodextrin,alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin,2-hydroxypropyl-alpha-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin,2-hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrinand combinations thereof.

Embodiment 90 is the emulsion of any one of embodiments 72-89, whereinthe solubilizer comprises 2-hydroxypropyl-beta-cyclodextrin.

Embodiment 91 is the emulsion of any one of embodiments 72-90, whereinthe polyoxyl oil is a polyoxyl castor oil.

Embodiment 92 is the emulsion embodiment 91, wherein the polyoxyl castoroil is polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combinationthereof.

Embodiment 93 is the emulsion of any one of embodiments 72-92, whereinthe lipophilic carrier is selected from the group consisting of castoroil, squalane, diethylene glycol monoethyl ether, propylene glycol,isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethylether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil,caprylic/capric triglycerides, medium chain triglycerides andcombinations thereof.

Embodiment 94 is the emulsion of any one of embodiments 72-93, whereinthe lipophilic carrier comprises castor oil.

Embodiment 95 is the emulsion of any one of embodiments 72-94, furthercomprising a surfactant selected from the group consisting ofpolysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxyl-40-stearate, tocopherol, and combinations thereof.

Embodiment 96 is the emulsion of embodiment 95, wherein the surfactantis present in an amount from about 0.05% to about 5% w/w.

Embodiment 97 is the emulsion of embodiment 95, wherein the surfactantis present in an amount from about 0.1% to about 1% w/w.

Embodiment 98 is the emulsion of embodiment 95, wherein the surfactantis present in an amount of about 0.5% w/w.

Embodiment 99 is the emulsion of any one of embodiments 72-98, furthercomprising an additional constituent selected from the group consistingof a thickener, a buffering agent, a tonicity agent, an antioxidant, andcombinations thereof.

Embodiment 100 is the emulsion of embodiment 99, wherein the thickenercomprises hydroxypropyl methylcellulose, sodium carboxymethylcellulose,or a combination thereof.

Embodiment 101 is the emulsion of any one of embodiments 99-100, whereinthe thickener is present in an amount from about 0.01% w/w to about 1.0%w/w.

Embodiment 102 is the emulsion of any one of embodiments 99-100, whereinthe thickener is present in an amount from about 0.05% w/w to about 0.5%w/w.

Embodiment 103 is the emulsion of any one of embodiments 99-100, whereinthe thickener is present in an amount of about 0.1% w/w.

Embodiment 104 is the emulsion any one of embodiments 99-103, whereinthe buffering agent comprises sodium citrate.

Embodiment 105 is the emulsion of any one of embodiments 99-104, whereinthe buffering agent is present in the emulsion in an amount sufficientto maintain the pH in the range of about 5.5 to about 6.5.

Embodiment 106 is the emulsion of any one of embodiments 99-105, whereinthe buffering agent is present in an amount from about 0.01% w/w toabout 1.0% w/w.

Embodiment 107 is the emulsion of any one of embodiments 99-105, whereinthe buffering agent is present in an amount from about 0.03% w/w toabout 0.06% w/w.

Embodiment 108 is the emulsion of any one of embodiments 99-105, whereinthe buffering agent is present in an amount of about 0.045% w/w.

Embodiment 109 is the emulsion of any one of embodiments 99-108, whereinthe antioxidant comprises edetate disodium, citric acid, or acombination thereof.

Embodiment 110 is the emulsion of any one of embodiments 99-109, whereinthe antioxidant comprises edetate disodium, and the edetate disodium ispresent in an amount from about 0.01% w/w to about 1.0% w/w.

Embodiment 111 is the emulsion of any one of embodiments 99-109, whereinthe antioxidant comprises edetate disodium, and the edetate disodium ispresent in an amount from about 0.05% w/w to about 0.5% w/w.

Embodiment 112 is the emulsion of any one of embodiments 99-109, whereinthe antioxidant comprises edetate disodium, and the edetate disodium ispresent in an amount of about 0.1% w/w.

Embodiment 113 is the emulsion of any one of embodiments 99-112, whereinthe antioxidant comprises citric acid, and the citric acid is present inan amount from about 0.001% to about 0.1% w/w.

Embodiment 114 is the emulsion of any one of embodiments 99-112, whereinthe antioxidant comprises citric acid, and the citric acid is present inan amount from about 0.005% to about 0.05% w/w.

Embodiment 115 is the emulsion of any one of embodiments 99-112, whereinthe antioxidant comprises citric acid, and the citric acid is present inan amount of about 0.015%.

Embodiment 116 is the emulsion of any one of embodiments 99-115, whereinthe tonicity agent comprises glycerin.

Embodiment 117 is the emulsion of any one of embodiments 99-116, whereinthe tonicity agent is present in an amount from about 0.01% w/w to about1% w/w.

Embodiment 118 is the emulsion of any one of embodiments 99-116, whereinthe tonicity agent is present in an amount from about 0.05% w/w to about0.5% w/w.

Embodiment 119 is the emulsion of any one of embodiments 99-116, whereinthe tonicity agent is present in an amount of about 0.1% w/w.

Embodiment 120 is an emulsion comprising:

-   -   about 0.2% w/w of a multikinase inhibitor selected from the        group consisting of nintedanib, axitinib, and pazopanib;    -   about 0.5% w/w of a polyoxyl castor oil;    -   about 0.25% w/w of castor oil;    -   about 10% w/w of 2-hydroxypropyl-beta-cyclodextrin; and    -   water.

Embodiment 121 is the emulsion of embodiment 120, wherein themultikinase inhibitor is axitinib.

Embodiment 122 is the emulsion of embodiment 120, wherein themultikinase inhibitor is nintedanib.

Embodiment 123 is the emulsion of embodiment 120, wherein themultikinase inhibitor is pazopanib.

Embodiment 124 is the emulsion any one of embodiments 120-123, whereinthe polyoxyl castor oil is polyoxyl-40 castor oil, polyoxyl-35 castoroil, or a combination thereof.

Embodiment 125 is the emulsion of any one of embodiments 116-124,further comprising polysorbate 80 in an amount of about 0.5% w/w.

Embodiment 126 is the emulsion of any one of embodiments 120-125,further comprising hydroxypropyl methylcellulose in an amount of about0.1% w/w.

Embodiment 127 is the emulsion any one of embodiments 120-126, furthercomprising sodium citrate in an amount of about 0.045% w/w.

Embodiment 128 is the emulsion of any one of embodiments 120-127,further comprising edetate disodium in an amount of about 0.1% w/w.

Embodiment 129 is the emulsion of any one of embodiments 120-128,further comprising citric acid in an amount of about 0.015%.

Embodiment 130 is the emulsion of any one of embodiments 120-129,further comprising glycerin in an amount of about 0.1% w/w.

Embodiment 131 is a method of prolonging the residence time of amultikinase inhibitor in the ocular surface comprising administering theemulsion of any one of embodiments 1-130 to an eye of a subject.

Embodiment 132 is the method of embodiment 131, wherein administeringcomprises applying the emulsion to the eye at least once per day.

Embodiment 133 is the method of embodiment 131, wherein administeringcomprises applying the emulsion to the eye at least twice per day.

Embodiment 134 is the method of embodiment 131, wherein administeringcomprises applying the emulsion to the eye at least three times per day.

Embodiment 135 is a method of treating an ocular condition, comprisingadministering the emulsion of any one of embodiments 1-130 to an eye ofa subject.

Embodiment 136 is the method of embodiment 135, wherein the ocularcondition is associated with angiogenesis.

Embodiment 137 is the method of embodiment 135, wherein the ocularcondition is selected from the group consisting of hyperemia,neovascularization, pterygium, pinguecula, glaucoma filtration surgeryand minimally invasive glaucoma surgery (MIGS), cornea transplantsurgery with graft rejection, graft versus host disease, dry eyedisease, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell'ssyndrome, Steven Johnson syndrome, viral infection (e.g. HSV-1),bacterial infection, fungal infection, parasitic infection, contact lensinduced neovascularization, ulceration, alkali burns, and stem celldeficiency.

Embodiment 138 is the method of any one of embodiments 131-137, whereinthe emulsion remains stable for at least 1 month at 40° C.

Embodiment 139 is the method of any one of embodiments 131-137, whereinthe emulsion remains stable for at least 6 months at 40° C.

Embodiment 140 is a method of preparing the emulsion of any one ofembodiments 1-130, the method comprising:

-   -   forming a primary emulsion;    -   reducing the droplet size of the primary emulsion to form a        nanoemulsion;    -   dissolving a multikinase inhibitor into a solution;    -   combining the nanoemulsion and solution to form a nanoemulsion        comprising the multikinase inhibitor; and    -   optionally, filtering the nanoemulsion comprising the        multikinase inhibitor.

Embodiment 141 is a method of preparing an emulsion, the methodcomprising:

-   -   forming a primary emulsion;    -   reducing the droplet size of the primary emulsion to form a        nanoemulsion;    -   dissolving a multikinase inhibitor into a solution;    -   combining the nanoemulsion and solution to form a nanoemulsion        comprising the multikinase inhibitor; and    -   optionally, filtering the nanoemulsion comprising the        multikinase inhibitor.

Embodiment 142 is the method of embodiment 140 or embodiment 141,wherein forming the primary emulsion comprises high shear mixing.

Embodiment 143 is the method of any one of embodiments 140-142, whereinreducing the droplet size comprising using a microfluidizer.

Embodiment 144 is the method of any one of embodiments 140-143, whereinfiltering comprises using a 0.2-micron filter.

Embodiment 145 is the method of any one of embodiments 140-144, whereinthe method further comprises filling the filtered nanoemulsion intosterile eye dropper bottles.

Embodiment 146 is the method of embodiment 145, wherein the sterile eyedropper bottles are multidose preservative free (MDPF) containers or lowdensity polyethylene (LDPE) unit dose containers.

Embodiment 147 is the method of any one of embodiments 140-146, whereinthe primary emulsion comprises:

-   -   a polyoxyl oil;    -   a lipophilic carrier; and    -   water.

Embodiment 148 is the method of any one of embodiments 140-147, whereinthe multikinase inhibitor is selected from afatinib, amuvatinib,axitinib, cabozantinib, canertinib, cediranib, ceritinib, crenolanib,crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib,gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib,lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib,pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib,sunitinib, tandutinib, tivantinib, tivozanib, trametinib, vandetanib,vatalanib, vemurafenib, or combinations thereof.

Embodiment 149 is the method of embodiment 148, wherein the multikinaseinhibitor is selected from axitinib, nintedanib, and pazopanib.

Embodiment 150 is the method of embodiment 148, wherein the multikinaseinhibitor is axitinib.

Embodiment 151 is the method of embodiment 148, wherein the multikinaseinhibitor is nintedanib.

Embodiment 152 is the method of embodiment 148, wherein the multikinaseinhibitor is pazopanib.

Embodiment 153 is the method of any one of embodiments 140 to 152,wherein solution further comprises a solubilizer.

Embodiment 154 is the method of embodiment 153, wherein the solubilizeris a cyclic polysaccharide.

Embodiment 155 is the method of embodiment 154, wherein the cyclicpolysaccharide is selected from the group consisting of cyclodextrin,alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin,2-hydroxypropyl-alpha-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin,2-hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrinand combinations thereof.

Embodiment 156 is the method of any one of embodiments 147 to 155,wherein the polyoxyl oil is a polyoxyl castor oil.

Embodiment 157 is the emulsion embodiment 156, wherein the polyoxylcastor oil is polyoxyl-castor oil, polyoxyl-35 castor oil, or acombination thereof.

Embodiment 158 is the method of any one of embodiments 147 to 157,wherein the lipophilic carrier is selected from the group consisting ofcastor oil, squalane, diethylene glycol monoethyl ether, propyleneglycol, isostearyl isostearate, isopropyl myristate, dipropylene glycoldimethyl ether, diethylene glycol, dipropylene glycol, mineral oil,silicone oil, caprylic/capric triglycerides, medium chain triglyceridesand combinations thereof.

Embodiment 159 is the method of any one of embodiments 147 to 158,wherein the primary emulsion further comprises a surfactant selectedfrom the group consisting of polysorbate 20, polysorbate 40, polysorbate60, polysorbate 80, polyoxyl-40-stearate, tocopherol, and combinationsthereof.

Embodiment 160 is the method of any one of embodiments 147-159, whereinthe multikinase inhibitor is nintedanib, the solubilizer is2-hydroxypropyl-beta-cyclodextrin, the lipophilic carrier is castor oil,and the polyoxyl oil is polyoxyl-35 castor oil, or a combinationthereof.

Embodiment 161 is the method of any one of embodiments 140 to 160,wherein the multikinase inhibitor is present in the primary emulsion anamount from about 0.001% w/w to about 10.0% w/w.

Embodiment 162 is the method of embodiment 161, wherein the multikinaseinhibitor is present in the primary emulsion an amount of about 0.01% toabout 1% w/w.

Embodiment 163 is the method of embodiment 161, wherein the multikinaseinhibitor is present in the primary emulsion an amount of about 0.1% toabout 0.5% w/w.

Embodiment 164 is the method of any one of embodiments 147 to 163,wherein the lipophilic carrier is present in the primary emulsion anamount from about 0.01% w/w to about 5.0 w/w.

Embodiment 165 is the method of embodiment 164, wherein the lipophiliccarrier is present in the primary emulsion in an amount from about 0.05%to about 1% w/w.

Embodiment 166 is the method of embodiment 164, wherein the lipophiliccarrier is present in the primary emulsion in an amount from about 0.1%to about 0.5% w/w.

Embodiment 167 is the method of any one of embodiments 147 to 166,wherein the polyoxyl oil is present in the primary emulsion in an amountfrom about 0.01% w/w to about 10% w/w.

Embodiment 168 is the method of embodiment 167, wherein the polyoxyl oilis present in the primary emulsion an amount from about 0.05% to about1% w/w.

Embodiment 169 is the method of embodiment 167, wherein the polyoxyl oilis present in the primary emulsion an amount from about 0.1% to about0.5% w/w.

Embodiment 170 is the method of any one of embodiments 140 to 169,wherein the primary emulsion further comprises a solubilizer, whereinthe solubilizer is present in the primary emulsion in an amount fromabout 1% w/w to about 20% w/w.

Embodiment 171 is the method of embodiment 170, wherein the solubilizeris present in the primary emulsion in an amount from about 5% to about15% w/w.

Embodiment 172 is the method of embodiment 170, wherein the solubilizeris present in the primary emulsion in an amount from about 8% to about12% w/w.

Embodiment 173 is the method of any one of embodiments 147 to 172,wherein the primary emulsion further comprises an additional constituentselected from the group consisting of a thickener, a buffering agent, atonicity agent, an antioxidant, and combinations thereof.

Embodiment 174 is the method of any one of embodiments 141-173, whereinthe filtered emulsion is the emulsion of any one of embodiments 1-130.

EXAMPLES Example 1. Emulsion Formulation Stability

Solution A and Emulsion B were prepared and stability was assessed.Solution A: 0.2% nintedanib in a solution system with 10%2-hydroxypropyl-beta-cyclodextrin. Emulsion B: 0.5% nintedanib in anemulsion system with 5% 2-hydroxypropyl-beta-cyclodextrin, castor oil,polysorbate 80, polyoxyl-35 castor oil. Stability data at acceleratedtemperatures (40° C., 50° C., and 60° C.) conditions can be used toextrapolate and predict room temperature long term storage. As shown inTable 2, the multikinase inhibitor remained stable in emulsion B whenstored at 40° C., 50° C., and 60° C. indicating that this formulationsystem could potentially maintain a 2 year shelf life, or longer, atroom temperature. The typical desired room temperature shelf life fortopical ocular solutions is 2 years.

TABLE 2 % Recovery normalized to T₀ Storage Initial FormulationCondition (T₀) 1-Day 4-Day 7-Day 14-Day 1-M 3-M 5-M 9-M Solution A 25°C. 100.0 NA NA NA NA 96.6 94.5 98.3 80.2 Solution A 40° C. 100.0 100.389.2 68.8 NA NA NA NA NA Emulsion B 40° C. 100.0 NA NA 97.9 97.3 99.0 NANA NA Emulsion B 50° C. 100.0 NA NA 97.3 98.9 97.4 NA NA NA Emulsion B60° C. 100.0 NA NA 93.2 96.2 95.7 NA NA NA

Example 2: Synergistic Effect of Emulsion System of Castor Oil,Polysorbate 80, Polyoxyl-35 Castor Oil and of2-Hydroxypropyl-BetaCcyclodextrin to the Solubility of Nintedanib

TABLE 3 Maximum CBT-001 (nintedanib free base) Solubility in SolventsMaximum solubility Solvents (mg/g) Castor oil 0.37 1% Polysorbate 800.25 Polyoxyl-35 castor oil 0.29 10% 2-Hydroxypropyl-beta-cyclodextrin2.0 Maximum theoretical possible solubility of nintedanib in the 0.91mixture of castor oil, polysorbate 80, and polyoxyl-35 castor oilMaximum theoretical possible solubility of nintedanib in the 2.91mixture of castor oil, polysorbate 80, polyoxyl-35 castor oil, and2-hydroxypropyl-beta-cyclodextrin Measured solubility of nintedanib inthe mixture of 3.4-5.0 nanoemulsion system of 0.25% castor oil, 1%castor oil, 1% polysorbate 80, and 2% polyoxyl-35-castor oil Measuredsolubility of nintedanib in the mixture of 10% 2- 7.9hydroxypropyl-beta-cyclodextrin and nanoemulsion system of 0.25% castoroil, 1% polysorbate 80, and 2% polyoxyl-35 castor oil

Per FDA guidance for Industry Drug Stability Guidelines, the stabilityof formulations can be predicted for long-term storage when it is storedat accelerated (high) temperature conditions. The stability data ataccelerated temperature conditions can be used to extrapolate andpredict long-term storage of drug product when stored at the recommendedstorage condition (ideally room temperature).

The maximum solubility of nintedanib in 10%2-hydroxypropyl-beta-cyclodextrin was about 0.2%. The 0.2% nintedanib in10% 2-hydroxypropyl-beta-cyclodextrin was demonstrated stable at roomtemperature for about 5 months and dropped below the acceptablestability specification (90% recovery) after 5 months. At theaccelerated storage condition (40° C.), it was not stable at Day 4. The% recovery of nintedanib dropped below 90% on Day 4 and below 70% on Day7. This indicates this 0.2% nintedanib in 10%2-hydroxypropyl-beta-cyclodextrin solution may have stability issue whenstore for 1- 2 years.

The 5% 2-hydroxypropyl-beta-cyclodextrin and nano-emulsion system wasused to improve the concentration and stability of nintedanib in theformulation system. 0.5% nintedanib in 5%2-hydroxypropyl-beta-cyclodextrin and a nano-emulsion system weredemonstrated as stable when stored at 40° C., 50° C., and 60° C. Thisindicates the 5% 2-hydroxypropyl-beta-cyclodextrin and nano-emulsionsystem had synergetic effects on stability of nintedanib in thenano-emulsion formulation system.

The maximum solubilities of nintedanib in each solvent are listed inTable 3. A theoretical maximum possible solubility of nintedanib in themixture can be extrapolated by assuming nintedanib is dissolved in eachsolvent, then each component is combined to make a mixture of allingredients. Calculated thus the theoretical maximum possible solubilityof nintedanib in the mixture would be 2.91 mg/g. Unexpectedly, in theformulation system of 10% 2-hydroxpropyl-beta-cyclodextrin and ananoemulsion of castor oil, 1% polysorbate 80 and 2% polyoxyl-35 castoroil, an improved solubility of nintedanib was achieved at 7.9 mg/g. Thisindicated the 10% 2-hydroxypropyl-beta-cyclodextrin and nanoemulsion ofcastor oil, 1% polysorbate 80 and 2% polyoxyl-35 castor oil hadsynergetic effects on solubility of nintedanib.

Example 3

Solubilizers for nintedanib were investigated according to the followingprocedure:

-   1. Tare 1.5mL Eppendorf tube-   2. Add nintedanib and record weight-   3. Add solubilizer and record weight-   4. Add water pH 5 (except F3 & F4) and record weight-   5. Beadbeater mix for 120 seconds-   6. Place on rotating mixer for overnight at ambient temperature-   7. Filter through 0.21.tm SPIN-X centrifuge filter-   8. Measure pH of filtrate-   9. Assay filtrate using CBT-001 standard solution

It was surprisingly found that vastly different results were obtainedfor the investigated solubilizers despite many of the investigatedsolubilizers having similar structural properties (see, e.g., Tables 4and 5). It was surprisingly discovered that solubilizers such as castoroil and polysorbate 80 (see, e.g., Table 3) were found to have highsolubilizing performance for nintedanib.

TABLE 4 Compositions screened (% wt) % WT F-1 F-2 F-3 F-4 F-5 F-6 F-7F-8 F-9 F-10 F-11 F-12 Nintedanib 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.50.5 0.5 0.5 Benzyl alcohol 1 Ethanol 1 Castor oil 99.5 Mineral oil 99.5BZK 1 Polysorbate 20 1 Polsorbate 80 1 Poloxamer 188 1 Poloxamer 407 1PEG 400 5 PEG 8000 2 Propylene glycol 1 WFI 98.5 98.5 98.5 98.5 98.598.5 98.5 94.5 97.5 98.5

TABLE 5 Solubility of nintedanib in various solubilizers SolubilizerNintedanib solubility (mg/g) pH BZA 0.01 5.6 EtOH 0.01 6.1 Castor oil0.37 — Mineral oil 0.00 — BZK 0.20 5.6 polysorbate 20 0.06 6.6polysorbate 80 0.25 6.7 PLXMR 188 0.01 6.5 PLXMR 407 0.01 6.3 PEG 400 0.17 5.6 PEG 8000 0.01 6.0 PG 0.01 6.0

Various emulsion systems were identified for investigation based on thesolubilizer results. It was surprisingly found that emulsion systemscombining castor oil, polysorbate 80 and polyoxyl-35 castor oil cansuitably solubilize nintedanib. As shown in Table 6 one of the emulsionsystems can surprisingly dissolve nintedanib to about 3-5 mg/ml, anamount much greater than the previously calculated upper theoreticallimit (see Table 3) for solubility of nintedanib in this combination.

TABLE 6 Solubility of nintedanib in a representative emulsion system. IDF70 lot 1 F70 lot 2 Castor Oil 1 1 Polysorbate 80 1 1 Polyoxyl-35 castoroil 2 2 Water 95 95 Nintedanib solubility 5 3.4

Example 4

Emulsion systems were identified for developing formulations fornintedanib and other multikinase inhibitors having physical chemicalproperties to nintedanib.

When oil and water are mixed together, the common phenomenon after ashort period of time is to form phase separation. Formulations withphase separation are unsuitable to use for certain ocular formulationssuch as eye drops. Various emulsion systems were investigated forphysical stability and uniformity for potential usage in the developmentof ocular formulations for nintedanib and other multikinase inhibitorshaving similar physical chemical properties. As shown in Table 7, it wassurprisingly found that some emulsion systems showed phase stabilitywhile others were not stable after three days, despite having componentswith similar properties. It has not been determined why some of thesystems are stable while others are not stable.

The below procedure was followed for investigating physical stability ofthe emulsion systems:

-   1. Adjust 100 mL of water to pH 5-   2. Tare 15 mL tube-   3. Add materials and record weights-   4. QS with water-   5. Vortex to mix for 1 minute-   6. High shear mix until a uniform emulsion is formed-   7. Record appearance and pH-   8. Aliquot each formulation into three 1.5 mL tubes-   9. Store at −20° C., 2-8° C. & 40° C. for 3 days-   10. Remove from storage and equilibrate to room temperature-   11. Record appearance-   12. Take only the vehicles which are uniform single-phase emulsions    and transfer to centrifuge-   13. Centrifuge for 10 minutes at 13K RPM.-   14. Record appearance-   15. Measure the pH of vehicles which are uniform single-phase    emulsions

TABLE 7 Stability results of various excipients combinations ID F13 F14F15 F16 F17 F18 F19 F20 Polysorbate 60 15 15 15 15 Polysorbate 80 4 4 44 ASpan 20 0.5 0.5 GMS 0.5 0.5 Myrj 52 7 7 Polyoxyl-35 5 5 castor oilCastor Oil 5 5 5 5 5 5 5 5 Water 79.5 79.5 73 75 90.5 90.5 84 86Observation of Uni- Sepa- Uni- Uni- Sepa- Sepa- Uni- Uni- formulation onform ration form form ration ration form form day 3

Emulsion system F20 was selected as a base system for furtherformulation development.

Example 5

In this example, it was determined that a cyclodextrin-based solubilizersystem was mixed with the selected castor oil, polysorbate 80 andpolyoxyl-35 castor oil-based emulsion system, the combination wascompatible and did not cause crashing out or phase separation.Furthermore, emulsion formulations containing the HP-beta-CD, castoroil, polysorbate 80, and polyoxyl-35 castor oil were found to achievesuperior stability over solution formulations. Without being bound byany particular theory, it is believed that the complex interactionsamong the drug and all these ingredients led to this superiority oversingle-component formulations. This surprising finding was determinedthrough extensive, comprehensive, and sophisticated experimentation thatexamined many ingredients sequentially to select the final combination.Superior compositions were determined after several rounds of testing.For example, Emulsion C showed very good stability at high temperatures(>40° C.) over several months, indicating the formulations will havegood stability during long-term storage at room temperatures. Theseresults were surprising because solution formulations were found to beunstable under the same conditions, and early emulsion formulationsinvestigated were also found to be less stable. As illustrated in Table8, just over half of nintedanib in the solution formulation remainedafter 1 month at 40° C., while nearly all nintedanib still remained inEmulsion C after 6 months under the same conditions. Table 8 also showedthat Emulsion C surprisingly kept nintedanib stable for at least 3months even at much higher temperatures of 50° C. and 60° C. Theseresults were surprising because solution formulations were found to beunstable under the same conditions, just over half of nintedanib in thesolution formulation remained after 4 weeks at 40° C., while allnintedanib still remained in Emulsion C after 6 months under the sameconditions (Table 8). The same kind of emulsion system also keptaxitinib, another MKI class of compound, stable for at least 3 months at40, 50 and 60° C., indicating the likelihood of long-term stability atroom temperature storage conditions (Table 9).

Method of Emulsion Formulation Development

The initial development included design, preparation and testing ofmultiple emulsion compositions for drug solubilization, droplet size andaccelerated emulsion physical stability (size change or aggregation)evaluation. Each test composition contained the basic componentsincluding API (e.g., nintedanib), oil, surfactant(s), solubilizer,emulsifier(s), lubricant, osmotic agent and water. From the initialwork, 2-3 compositions were selected, modified as needed and evaluatedfor viscosity, osmotic pressure and emulsion physical stability. Oneexemplary composition was selected for additional evaluation aftermeeting pre-set requirements.

A pilot-scale manufacturing process was developed to produce thePrototype Formulation at 0.1-1 L batch size. The manufacturing processincluded: (1) dissolution of API into a primary emulsion using a highshear mixer, (2) reduction of droplet size to the size target using amicrofluidizer, (3) passage of the nanoemulsion through a 0.2-micronfilter, and (4) filling the nanoemulsion into sterile eye dropperbottles (Multidose Preservative Free Containers or MDPF and LDPE unitdose containers) in a biosafety hood. Batches (about 250 mL) of thePrototype Formulation were prepared at each of the 4 strengths (0,0.05%, 0.2% and 0.5%). Using aseptic technique, Prototype Formulationbatches were loaded into 5.5 mL Aptar dropper bottles (3 mL/bottle) or aLDPE unit dose container (0.3 mL/unit).

For each batch strength, formulations were tested for pH, appearance(visual and microscopic), osmotic pressure, viscosity, droplet size, APIconcentration and impurity. These test results were used as the initialvalues for the stability testing (T=0). For each batch strength, thePrototype Formulations were placed in stability chambers set at varioustemperatures for various time periods. Stability tests for appearance(visual and microscopic), particulate matter (count), droplet size, drugconcentration, impurities/degradation products, osmolarity, and pH wereperformed at selected time points.

Formulations Emulsion C, F134, and F135 were prepared as follows:

Part 1: Oil/Surfactant Emulsion

-   1. Tare a 50 mL Falcon Tube-   2. Add 1.25 g of castor oil-   3. Add 0.250 g of tween 80-   4. Add 0.250 g of polyoxyl-35 castor oil-   5. Heat the mixture to 50° C. in a sonicator then vortex until    uniform and clear-   6. Add 13.25 g of deionized water-   7. Homogenize the mixture at high speed until the oil droplet size    is below 100 nm.-   Mixing speed: 4000 RPM-   Mixing time: 30 minutes

Emulsion C Z-Avg: 35 nm F-134 Z-Avg: 37 nm F-135 Z-Avg: 33 nm Part 2:Nintedanib, Axitinib and Pazopanib in HP-Beta-CD Solution

-   1. Tare a 50 mL Falcon tube-   2. Add 25 g of DI-water to a container.-   3. While stirring add 5.0 g of HP-beta-CD and stir until completely    dissolved.-   4. Add 0.008 g of citric acid and stir until completely dissolved.-   5. Add 0.100 g of API to the mixture-   6. Sonicate the mixture for 15 minutes and vortex until dissolved    completely-   7. Add 0.023 g of sodium citrate to the mixture and mix until    completely dissolved.-   8. Add 0.050 g of trisodium EDTA to the mixture and mix until    completely dissolved.-   9. While stirring the mixture, slowly add 0.050 g of HPMC and mix    until completely dissolved.

Part 3. Formulations Emulsion C, F134, and F135

-   1. Tare a 100 mL glass bottle-   2. Add aqueous solution (part 2)-   3. Add oil emulsion (part 1)-   4. Add 5 g of deionized water-   5. Add 0.05 g of glycerin to the mixture and mix well.-   6. Adjust the pH to 6.0 using 1N NaOH or 1N HCL.

Emulsion C Initial pH: 6.66 Final pH: 5.87 F-134 Initial pH: 2.51 FinalpH: 6.12 F-135 Initial pH: 1.24 Final pH: 6.03

-   7. QS to 50 g of deionized water and mix

Part 4. Filter and Fill

-   1. Aseptically filter formulations through a sterile 0.2 μm syringe    filter into a sterile container-   2. Aseptically fill 5 mL of formulation into 5×10 mL Type 1 glass    vials-   3. Cap vials with rubber septum and crimp seal-   4. Store 2 vials of each formulation at 2-8, 25, 40, 50 and 60° C.-   5. Monitor for ppt over 1 week

Final concentrations of CBT-001 (nintedanib) and excipients in theformulations were determined for the following formulations: Solution A:0.2% nintedanib in a solution system with 10%2-hydroxypropyl-beta-cyclodextrin. Emulsion C: 0.2% nintedanib in anemulsion system with 10% 2-hydroxypropyl-beta-cyclodextrin, castor oil,polysorbate 80, polyoxyl-35 castor oil.

TABLE 8 Accelerated in-lab stability of Emulsion C in comparison toSolution A. The percentage of remaining nintedanb is shown at each timepoint. Storage % Recovery normalized to T₀ Formulation Condition Initial(T₀) 14-Day 1-M 3-M 5 or 6-M 9-M Solution A 25° C. 100.0 NA 101.1 98.2 94.9* 81.2 Solution A 40° C. 100.0 NA 55.2 62.1  69.6* NA Emulsion C25° C. 100.0 101.4 99.9 99.1 103.3{circumflex over ( )} Emulsion C 40°C. 100.0 101.2 100.9 105.0 112.0{circumflex over ( )} NA Emulsion C 50°C. 100.0 101.8 101.4 110.7 NA NA Emulsion C 60° C. 100.0 100.7 101.0113.9 NA NA *5 month; {circumflex over ( )}6 month

In addition to nintedanib, another multikinase inhibitor, axitinib, wasinvestigated and surprisingly showed good stability at high temperaturesover 3 months in a similar emulsion (Table 9). The experiment showedthat multikinase inhibitors with similar physical and chemicalproperties, e.g., nintedanib and axitinib can be formulated in certainsimilar emulsion formulations for long-term storage.

TABLE 9 Accelerated in-lab stability of axitinib in a representativeemulsion (F134). The percentage of remaining axitinib is shown at eachtime point. Day 1 Formulation Temp (T₀) Week 2 Week 4 Week 8 Week 12F134 40° C. 100 97.9 100.3 98.3 105.1 (axitinib 50° C. 100 99.7 101.899.5 112.9 emulsion) 60° C. 100 102.8 102.5 100.0 114.0

Example 6

Emulsion formulations, used at the same strength, are superior to asolution formulation in terms of efficacy and ocular pharmacokineticprofiles in a rabbit model of corneal neovascularization (CNV) whileemulsion formulation and solution formulation share similar safetyprofile. The solution formulation used in the study had already beenshown to be safe and efficacious in a human clinical trial.

Study Summary

The study evaluated efficacy of emulsion and solution formulations inthe inhibition of hyperemia and neovascularization in the corneal suturerabbit model following 7 days of topical ocular BID (twice daily) dosingof 0.2% nintedanib Emulsion, 0.05% axitinib Emulsion and pazopanibEmulsion or TID (three times daily) dosing of 0.2% nintedanib Solutionand vehicle Emulsion. The solution was the solution described in Example5. The emulsion was very similar to Emulsion C in Example 5. Inaddition, the systemic and ocular pharmacokinetics and oculartolerability were evaluated in these animals.

All the formulations tested were well tolerated in the eye andsystemically. Even though rabbits were dosed less frequently at twice aday (BID) with 0.2% nintedanib emulsion compared to three times a day(TID) with 0.2% nintedanib solution, the 0.2% nintedanib emulsion BIDsurprisingly showed similar or better efficacy than the 0.2% nintedanibsolution, TID, as shown in FIG. 2 . At Day 10, the efficacy of theemulsion and solution are similar. At Day 12, the emulsion wasstatistically more effective than the solution (p=0.0025).

The ocular pharmacokintic profile indicated that the emulsion candeliver more drug to the target tissues of conjunctiva and cornea withhigher C_(max) and AUC (Table 10). A further analysis of theconcentration/IC50 ratio over time indicates that the emulsion can havemore effective inhibition of the target VEGFR2 since a ratio >10 wouldalmost completely inhibit the target (Table 11). This demonstrated 0.2%nintedanib emulsion is superior than 0.2% nintedanib solution ondelivering more drugs to the ocular surface to achieve better efficacyand longer duration.

TABLE 10 PK comparison between the nintedanib emulsion and solutionSolution vs emulsion formulations PK comparison C_(max) T_(max)AUC_(0-tlast) (ng/g) (hr) (ng*h/g) Conjunctiva 0.2% solution TID 438 ±82 0.5 1620 0.2% emulsion BID  763 ± 170 0.5 3982 Cornea 0.2% solutionTID  704 ± 884 0.5 3982 0.2% emulsion BID 1142 ± 326 0.5 8316

TABLE 11 Concentration/VEGFR2 IC₅₀ ratio of the two nintedanibformulations Concentration/VEGFR2 IC50 ratio Time (h) 0.5 2 6 12Conjunctiva 0.2% solution TID 38.6 23.6 5.6 3.7 0.2% emulsion BID 67.348.2 19.1 18.5 Cornea 0.2% solution TID 42.4 53.4 62.1 8.5 0.2% emulsionBID 100.7 62.6 70.0 36.8

Example 7

The effectiveness of the surfactants PEG40 Stearate and polyoxyl-35castor oil was investigated for performance in the emulsion systems. Thecompositions investigated are shown in Table 12.

TABLE 12 Composition of formulations F70 and F72. F70 F72 CBT001 (mg/mL)10 10 Castor Oil 1 1 Polysorbate 80 1 1 PEG40 Stearate 2 Polyoxyl-35castor oil 2 HP-beta-CD Water 95 95

Formulations F70 and F72 (Table 12) were prepared and investigated asfollows.

-   1. Adjust the pH 100 mL of water to pH2.0 with 1N HCL pH.-   2. Label 15 mL conical tube.-   3. Tare conical tube.-   4. Add water and record weight.-   5. Vortex into a clear solution.-   6. Add Tween 80 & Polyoxyl-35 castor oil or PEG40 Stearate and    record weight.-   7. Add castor oil and record weight.-   8. Vortex for 1 minute.-   9. High shear mix into a clear or uniform solution.-   10. Add API.-   11. Place conical tube in an ice bath.-   12. High shear mix for 30 minutes.-   13. After 30 minutes, centrifuge to force non-dissolved API to    bottom of tube.-   14. Collect 50μL from top of emulsion and test dropt size by LLS.-   15. If greater than 200nm, continue high shear mixing and retest.-   16. Record final droplet size.-   17. Measure pH.-   18. If below pH 6 then adjust pH to 6 with 1N NaOH. If pH between    6-8, do not adjust.-   19. Filter through 0.2 μm syringe filter.-   20. Measure pH, particle size of filtrate.-   21. Assay using CBT-001 (nintedanib) standard solution.

The results of this experiment are shown in Table 13. Because a higherconcentration of nintedanib was achieved in formulation F70 than informulation F72, the combination of Polyoxyl-35 castor oil andPolysorbate 80 is believed to be a better surfactant system compared tothe combination of PEG40 Stearate and Polysorbate 80 for emulsifyingcastor oil to dissolve nintedanib.

TABLE 13 Results F F70 F72 Nintedanib concentration (mg/mL) 5.2 1.5

1-26. (canceled)
 27. An emulsion comprising: about 0.01% to about 1% w/wof nintedanib; about 0.3% to about 0.7% w/w of polyoxyl-35 castor oil;about 0.1% to about 0.5% w/w of castor oil; about 8% to about 12% w/w of2-hydroxypropyl-beta-cyclodextrin; about 0.1% to about 1% w/w ofpolysorbate 80; and water.
 28. The emulsion of claim 27, wherein thepolyoxyl-35 castor oil is present in an amount of about 0.5% w/w. 29.The emulsion of claim 27, wherein the castor oil is present in an amountof about 0.25% w/w.
 30. The emulsion of claim 27, wherein the2-hydroxypropyl-beta-cyclodextrin is present in an amount of about 10%w/w.
 31. The emulsion of claim 27, wherein the polysorbate 80 is presentin an amount of about 0.5% w/w.
 32. The emulsion of claim 27, furthercomprising an additional constituent selected from a thickener, abuffering agent, an antioxidant, a tonicity agent, or a combinationthereof.
 33. The emulsion of claim 32, wherein the emulsion comprises athickener, and wherein the thickener is present in an amount of about0.05% to about 0.5% w/w.
 34. The emulsion of claim 33, wherein thethickener comprises hydroxypropyl methylcellulose, sodiumcarboxymethylcellulose, or a combination thereof.
 35. The emulsion ofclaim 32, wherein the emulsion comprises a buffering agent, and whereinthe buffering agent is present in an amount of about 0.01% to about 1.0%w/w.
 36. The emulsion of claim 35, wherein the buffering agent comprisessodium citrate, citric acid, or a combination thereof.
 37. The emulsionof claim 32, wherein the emulsion comprises an antioxidant, and whereinthe antioxidant comprises edetate disodium present at an amount of about0.01% to about 1.0% w/w.
 38. The emulsion of claim 32, wherein theemulsion comprises a tonicity agent, and wherein the tonicity agent ispresent in an amount of about 0.01% to about 1.0% w/w.
 39. The emulsionof claim 38, wherein the tonicity agent comprises glycerin.
 40. A methodof treating an ocular indication, comprising administering the emulsionof claim 27 to an eye of a subject.
 41. The method of claim 40, whereinthe ocular condition is associated with angiogenesis.
 42. The method ofclaim 40, wherein the ocular condition is hyperemia, neovascularization,pterygium, pinguecula, glaucoma filtration surgery, minimally invasiveglaucoma surgery (MIGS), cornea transplant surgery with graft rejection,graft versus host disease, dry eye disease, atopic conjunctivitis,rosacea, ocular pemphigoid, Lyell's syndrome, Steven Johnson syndrome,viral infection, bacterial infection, fungal infection, parasiticinfection, contact lens induced neovascularization, ulceration, alkaliburns, or stem cell deficiency.